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The persistence of somatosensory and auditory pathway evoked potentials in severe hypoglycemia in the cat
Electroencephalograptzv and clinical Neurophysiologv, 1985, 61:161 Elsevier Scientific Publishers Ireland, Ltd.
164
161
Short communication THE P E R S I S T E N C E OF S O M A T O S E N S O R Y A N D A U D I T O R Y PATHWAY EVOKED P O T E N T I A L S IN SEVERE HYPOGLYCEMIA IN THE CAT t E. D E U T S C H *, S. F R E E M A N **, H. S O H M E R **,2 and M. G A F N I ** * Department of E.N. 72, Bikur Cholim Hospital, and ** Department of Physiology, Hebrew University- Hadassah Medical School, 91010 Jerusalem (Israel)
(Accepted for publication: March 26, 1985)
Summary In a previous study it was shown that during severe insulin-induced hypoglycemia in rats and cats (0.38 m m o l / l , i.e., 6.8 mg% and 0.8 mmol/1, i.e., 14 mg% respectively) with isoelectric EEG, the latency and amplitude of the auditory nerve-brain-stem evoked responses were not affected. In the present study on cats, the above evoked responses were complemented by recording in addition the cortical auditory evoked potential and the peripheral, brain-stem and cortical components of the somatosensory evoked potentials. Each of these evoked potentials remained in the presence of 0.75 mmol/1 glucose in plasma. The persistence of the somatosensory cortical evoked potential was unexpected since two other groups have reported the disappearance of this potential during hypoglycemia. The types of neuronal activity which can still be recorded in severe hypoglycemia are probably generated by neuronal structures with lower metabolic demands such as axons and oligosynaptic pathways, surviving on the consumption of endogenous substrates with compensatory elevation of local cerebral blood flow. Keywords: evoked potentials - - auditory - - somatosensory --. brain-stem auditory pathway (BAP) - - hypoglycemia - - cortical EP
In a previous study (Deutsch et al. 1983) it was shown that the evoked potentials of the auditory nerve and brain-stem auditory pathway (BAP) could still be recorded during severe insulin-induced hypoglycemia. In order to examine the possible differential effects of severe hypoglycemia on the functional activity of an additional sensory pathway and on electrical activity generated at different levels of the nervous system, a further study was conducted in which the somatosensory and auditory evoked potentials (peripheral nerve, brain-stem and cortical components) and the EEG were recorded in cats in a state of severe insulin-induced hypoglycemia.
Methods
These experiments were performed on 16 adult cats. Following a period of fasting of about 18 h, the cats were anesthetized by intraperitoneal injection of 40 m g / k g pentobarbital. Cannulae were inserted into the trachea, a femoral vein and both femoral arteries (one artery for continuous monitoring of
J A preliminary report of this study was presented at the regional meeting of the International U n i o n of Physiological Sciences, Jerusalem, August, 1984. Supported in part by the Ministry of Science, Israel. 2 Please address all correspondence to: Prof. H. Sohmer, Dept. of Physiology, Hebrew University-Hadassah Medical School, POB 1172, Jerusalem 91010, Israel.
arterial blood pressure and the second for blood sampling). The EEG was recorded between 2 copper screws inserted into the fronto-parietal skull on either side of the midline. In the first 11 cats in this series the evoked potentials were elicited and recorded by means of a laboratory-assembled modular evoked response system. The somatosensory stimulus was a 50 /~sec, 2 / s e c electrical pulse delivered by needle electrodes to the fore paw. The intensity was adjusted to elicit fore paw movement. The early components (peripheral nerve and brain-stem) of the somatosensory evoked potentials (SEPs) were recorded as the potential difference between a scalp needle electrode and a second needle electrode in the shoulder ipsilateral to the stimulated limb, filtered (200-3000 Hz), averaged using a 10 msec window (40 /~sec/address) and displayed scalp positive up. The cortical SEP (CSEP) was recorded between the contralateral skull screw electrode and the ipsilateral shoulder needle electrode, filtered (0.2-40 Hz), averaged using a 100 msec window (390 ~sec/address) and displayed scalp positive up. The auditory stimulus was a click at intensity 60 dB above the threshold of normal h u m a n listeners, i.e., 60 dB HL. The early components of the auditory evoked potentials, that is, the auditory nerve-brain-stem evoked response (BAP) to 20/sec clicks was recorded using the same electrodes, filter bandpass, averager window and display as the SEP. The cortical auditory evoked potential (CAEP) to 2 / s e c clicks was recorded, filtered, averaged and displayed as the CSEP. The evoked potentials in the remaining 5 cats were elicited and recorded by means of a Neurolab 2000 (Microshev Ltd.,
0013-4649/85/$3.30 © 1985 Elsevier Scientific Publishers Ireland, Ltd.
162 Israel). A recording needle electrode was placed in the skin of the scalp overlying the contralateral somatosensory cortex and a second needle electrode was placed in the neck. The CSEP was elicited by 4 / s e c 50 ,~sec pulses and the recorded activity was filtered 30-3000 Hz and averaged with a 51 msec window. The SEP was filtered 30-3000 Hz or 200-3000 Hz and averaged using a 12.5 msec window. The BAP to 2 0 / s e c clicks was filtered (200-3000 Hz) ~/nd averaged (12.5 msec window). The C A E P to 2 / s e c clicks was filtered (3-40 Hz) and averaged (382 msec window). Blood glucose levels were determined every 30 rain using the glucose oxidase kit of Boehringer (Werner et al. 1970). Experimental procedure Following control recording (EEG and each of the EPs) and arterial blood sampling (for glucose determination), an initial dose of insulin was injected. Smaller additional doses were given every half hour. The total dosage ranged between 230 and 1600 I U / k g with an average of 490 I U / k g . Electrical records and blood samples were obtained at least every 30 min. In order to maintain the hypoglycemic state for long periods the cats were paralysed (gallamine) and artificially ventilated and were given infusions of dopamine when necessary to maintain mean arterial blood pressure greater than 100 m m Hg. Body temperature was maintained at 37-38°C. The peak latency and peak-to-peak amplitude of the following EPs were evaluated: the BAP wave at about 2.8 msec; CAEP the prominent vertex positive wave with a latency of about 18 msec; SEP - - the 5 - 6 msec wave (shown to be of brain-stem origin by Nakanishi et al. 1982); CSEP - - the vertex positive 10-12 msec wave, The average change in latency and amplitude of each of these waves between the control and final severe hypoglycemic state was calculated and a paired t test was used to determine whether these latency and amplitude changes were significant.
Results
The results of a typical experiment are shown in Figs. 1 and 2 (Neurolab 2000). It can be seen that the CAEP (Fig. 1) and CSEP (Fig. 2) could still be evoked in the presence of a blood glucose level of 0.6 mmol/1 (10.8 rag%). In the CSEP trace some of the SEPs can be seen as small waves which were actually studied with a 12.5 msec window. The final EP traces and glucose levels were obtained 334 rain after the initial insulin administration (total received 900 I U / k g ) ; the EEG became isoelectric 93 ¢ min after insulin administration: the experiment was continued for an additional 244 rain and the glucose level was below 1.66 m m o l / l (30 rag%) for 290 rain. The average results of all of the experiments were similar, The blood glucose level fell below 1.66 m m o l / I 45 rain on Blood Gtucose (rnrnel / II
ABR
3.3
Cortical
~
j
o.6
-
~ ] 1.6 #V 1 msec
~ . ] l 2 ~V 30 msec
Fig. 1. Auditory evoked potentials before (3.3 m m o l / I glucose) and during severe hypoglycemia (0,6 retool/l: 10.8 mg%). The auditory nerve and brain-stem evoked responses are shown on the left and the cortical response on the right. The stimulus is simultaneous with the beginning of the trace.
TABLE I Evoked potential parameter changes induced during severe hypoglycemia (average and standard deviation). Gluca~e let~els
Initial
mmol/I (rag%)
4.6 + 1.2 (83.4_+22.3)
Final 0.75_+ 0,26 (13.5 _+ 4.7)
Auditoty EP %,5 latency %,5 amplitude
BA P +4.8_+14.3 -10.5_+83.2
P NS NS
CA EP - 1 6 . 3 _+25.6 - 1 4 . 5 _+60.2
P < 0.05 NS
SEP --2.8_+ 9.2 - 15.7 _+81.3
P NS NS
CSEP - 2 . 6 _+25.0 - ] 6,8 _+64.1
P NS NS
Somatosensory EP %A latency %,5 amplitude
163
Peripheral
Brood
Cortical
Glucose ( ram01 I [ )
3.3
0.6
~.]81 I rnsec
~v
~_] ~ ~V l, rnsec
Fig. 2. Somatosensory evoked potentials before and during severe hypoglycemia in the same experiment shown in Fig. 1. Note the continued relatively unaltered presence of each of the evoked potentials during hypoglycemia. The stimulus is simultaneous with the beginning of the trace. average following the initial insulin administration. The EEG became isoelectric in each cat. This occurred at an average glucose level of 1 m m o l / l , 80 min after insulin administration and the experiment was continued for an additional average period of 134 min. The average post-insulin duration of the experiments was 214 min (range: 120-334 min). There were large variations from experiment to experiment in the direction and magnitude of the amplitude and latency changes of the various EP waves. These changes (Table I) were not statistically significant except for the latency decrease of the CAEP. In no case did any of the EPs become isoelectric even at the lowest glucose blood levels. Discussion
The results of this study have shown that during hypoglycemia (0.75 mmol/1), the only significant EP change is a small decrease in the latency of the cortical AEP. All other EPs (SEP and AEP) including peripheral nerve, brain-stem and cortical components were not altered. This resistance of the AEP was originally considered paradoxical since other studies had demonstrated high metabolic rates in auditory regions of the brain (highest levels of glucose utilization (Des Rosiers et al. 1974) and highest levels of regional cerebral blood flow (Reivich et al. 1969)). However, it is now understood that these signs of elevated metabolism were probably induced by the ambient noise of the laboratory environment (Kennedy et al. 1975). The persistence of the somatosensory cortical evoked potential was unexpected since two other groups have reported the disappearance of this potential during hypoglycemia. Brierley and his group (Brierley et al. 1971; Meldrum et al. 1971), in a study devoted mainly to the induced neuropathological structural changes, recorded the cortical SEP in monkeys. The average blood glucose levels and durations of the experiments were similar to those in this study. Nevertheless, Meldrum et al. (1971) report the occurrence of cortical SEP silence 14 min prior to the EEG silence. They reported microvacuolation and ischemic cell changes in the neocortex, hippocampi and stria-
tum in most of the animals studied. Agardh and Rosdn (1983), studying mainly the induced alterations in cerebral metabolism, recorded the cortical SEP in rats and reached blood glucose levels of 0.6 m m o l / l and this state was maintained for up to 60 min. They also reported that in all cases the cortical SEP disappeared before the EEG. In the same animal model it has been shown that such hypoglycemia is accompanied by severe perturbations of cerebral energy metabolism (Lewis et al. 1974a, b). This finding of the disappearance of a cortical EP before the EEG becomes silent contradicts the results of this and several other studies which have reported the disappearance of the EEG before the cortical evoked potentials (e.g., Meldrum and Brierley 1969: Shelburne et al. 1976; Colin et al. 1978). Thus, it is difficult to reconcile the results of this laboratory, showing that in cats there was no case in which the cortical SEP (or the cortical AEP and brain-stem SEP and AEP) became electrically silent even when continued for an average period of 134 rain following EEG silence, with the results of Meldrum et al. (1971) and Agardh and Ros6n (1983) who report its disappearance prior to that of the EFG during similar degrees and shorter durations of hypoglycemia. It would appear from our study that the sites and neuronal structures responsible for generating the evoked potentials studied are still capable of generating their evoked electrical activity in spite of the severely decreased content of glucose in arterial blood, in the presence of an isoelectric EEG and in spite of the reported irreversible neuronal damage (Brierley et al. 1971) and marked perturbation of energy state. The continued generation of these types of evoked electrical activity may be due to the fact that they are generated by axons with the involvement of a relatively small number of synapses. This may be facilitated by the observed compensatory elevation of local cerebral blood flow (as long as adequate systemic arterial blood pressure is maintained) (MacMillan et al. 1974; AbdulR a h m a n et al. 1980:Siesj6 et al. 1983). In addition, it has been shown that neurons may continue to function in spite of decreased glucose availability by consumption of other endogenous substrates such as most components of the citric acid cycle, amino acids (Norberg and Siesj5 1976) and finally phospholipids, leading perhaps to the structural neuronal damage reported (Agardh et al. 1981). In conclusion, the evoked activity which can still be recorded in severe insulin-induced hypoglycemia is probably generated by neuronal structures with lower metabolic dem a n d s such as axons and oligosynaptic pathways while the compensatory mechanisms of elevated blood flow and consumption of endogenous substrates are sufficient to ensure their continued function. Resume Maintenance des potentiels ~voqubs somatosensoriels et audittf~ au cours d'une hypoglyc~mie sky,re chez le chat
Dans une 6tude pr6c6dente il a 6t6 d6montr6 que durant une hypoglyc6mie s6v6re induite par l'insuline chez des rats et
164
des chats (0,38 m m o l / l soit 6,8 rag% et respectivement 0,8 m m o l / l soit 14 mg%) avec EEG iso61ectrique il ne s'dtait pas produit de modifications de latence et d'amplitude des r6ponses evoqu6es auditives du tronc c6r~bral. Dans 1'6tude pr~sente sur le chat, les r6ponses 6voqu6es mentionnO,es ci-dessus ont 6t6 compl6t6es par l'enregistrement du potentiel evoqu6 auditif cortical el p6riph6rique, et des potentiels 6voquds somatosensoriels p6riphOriques, du tronc cdr6bral et du cortex. Chacun de ces potentiels 6voquds est demeur6 en pr6sence de 0,75 mmol/1 de glucose dans le plasma. La persistance des potentiels 6voquds somatosensoriels corticaux 6tait inattendue du fair que deux autres groupes avaient d6crit la disparition de ces potentiels durant l'hypoglyc6mie. Les types d'activit6 des cellules nerveuses pouvant Etre encore enregistr6s lors d'hypoglyc6mies s6v
References AbduI-Rahrnan, A., Agardh, C.D. and Siesj6, B.K. Local cerebral blood flow in the rat during severe hypoglycemia, and in the recovery period following glucose injection. Acta physiol, scand., 1980, 109: 307-314. Agardh, C.D. and Ros6n, I. Neurophysiological recovery after hypoglycemic coma in the rat: correlation with cerebral metabolism. J. Cereb. Blood Flow Metab., 1983, 3: 78-85, Agardh, C.D., Chapman, A.G., Nilsson, B. and SiesjO, B.K, Endogenous substrates utilized by rat brain in severe insulin-induced hypoglycemia. J. Neurochem., 1981, 36: 490-500. Brierley, J.B., Brown, A.W. and Meldrum, B.S. The nature and time course of the neuronal alterations resulting from oligaemia and hypoglycaemia in the brain of Macaca mulatta. Brain Res., 1971, 25: 483-499. Colin, F., Bourgain, R. and Manil, J. Progressive alteration of somatosensory evoked potential waveforrns with lowering of cerebral tissue PO z in the rabbit. Arch. int. Physiol. Biochem., 1978, 86: 677-679. Des Rosiers, M.H., Kennedy, C., Patlak, C.S., Pettigrew, K.D. and Sokoloff, L. Relationship between local cerebral blood flow and glucose utilization in the rat. Neurology (Minneap.), 1974, 24: 389. Deutsch, E., Sohmer, H,, Weidenfeld, J., Zelig, S. and Chowers, 1. Auditory nerve-brain stem evoked potentials and EEG during severe hypoglycemia. Electroenceph. clin. Neurophysiol., 1983, 44: 714-716. Kennedy, C.. Des Rosiers, M.H., Jehle, J.W., Reivich, M., Sharpe, F. and Sokoloff, L. Mapping of functional neural pathways by autoradiographic survey of local metabolic rate with [14C]deoxyglucose. Science, 1975, 187: 850-853.
Lewis, L.D., Ljunggren, B., Norberg, K. and Siesj6, B.K. Changes in carbohydrate substrates, amino acids and ammonia in the brain during insulin-induced hypoglycemia. J. Neurochem., 1974a, 23: 659-671. Lewis, L.D., Ljunggren, B., Ratcheson, R.A. and Siesj~. B.K. Cerebral energy state in insulin-induced hypoglycemia, related to blood glucose and to EEG. J. Neurochem., 1974b, 23: 673-679. MacMillan, V., Salford, L.G, and Siesjo, B.K. Metabolic state and blood flow in rat cerebral cortex, cerebellum and brainstem in hypoxic hypoxia. Acta physiol, scand., 1974, 92: 103=113. Meldrum, B.S. and Brierley, J.B. Brain damage in the rhesus monkey resulting from profound arterial hypotension. II. Changes in the spontaneous and evoked electrical activity of the neocortex, Brain Res., 1969, 13: 101-118. Meldrum, B.S., Horton, R.W. and Brierley. J.B. Insulin-induced hypoglycemia in the primate: relationship between physiological changes and neuropathology. In: J.B. Brierley and B.S. Meldrum (Eds.), Brain Hypoxia. Heinemann Medical Books, London, 1971: 207-224. Nakanishi, T., Tamaki, M., Arasaki, K. and Kudo, N. Origins of the scalp-recorded somatosensory far field potentials in man and cat. In: P.A. Buser, W.A. Cobb and T. O k u m a (Eds.), Kyoto Symposia (EEG Suppl. No. 36). Elsevier, Amsterdam, 1982: 336-348. Norberg, K. and Siesj6, B.K. Oxidative metabolism of the cerebral cortex of the rat in severe insulin-induced hypoglycemia. J. Neurochem., 1976, 26:345 352. Reivich, M., Jehle, J.. Sokoloff, L. and Kety, S.S. Measurement of regional cerebral blood flow with antipyrine-14C in awake cats. J. appl. Physiol., 1969, 27: 296-300. Shelburne, J., McLaurin, A.N. and McLaurin, R.L. Effects of graded hypoxia on visual evoked responses of rhesus monkeys. In: R.L. McLaurin (Ed.), Head Injuries. Grune and Stratton, New York, 1976: 89-93. Siesj6, B,K., Ingvar, M. and Pelligrino, D. Regional differences in vascular autoregulation in the rat brain in severe insulininduced hypo-glycemia. J. Cereb. Blood Flow Metab., 1983, 3: 478-485. Sokoloff, L. Local cerebral energy metabolism: its relationships to local functional activity and blood flow. Bull, Schweiz, Akad, med. Wiss., 1980, 36: 71-91. Werner, W., Rey, H.G. and Wielinger, H. Properties of a chromogen for the determination of glucose in blood according to the G O D / P O D method, Z. anal. Chem., 1970, 252: 224-228.
164
161
Short communication THE P E R S I S T E N C E OF S O M A T O S E N S O R Y A N D A U D I T O R Y PATHWAY EVOKED P O T E N T I A L S IN SEVERE HYPOGLYCEMIA IN THE CAT t E. D E U T S C H *, S. F R E E M A N **, H. S O H M E R **,2 and M. G A F N I ** * Department of E.N. 72, Bikur Cholim Hospital, and ** Department of Physiology, Hebrew University- Hadassah Medical School, 91010 Jerusalem (Israel)
(Accepted for publication: March 26, 1985)
Summary In a previous study it was shown that during severe insulin-induced hypoglycemia in rats and cats (0.38 m m o l / l , i.e., 6.8 mg% and 0.8 mmol/1, i.e., 14 mg% respectively) with isoelectric EEG, the latency and amplitude of the auditory nerve-brain-stem evoked responses were not affected. In the present study on cats, the above evoked responses were complemented by recording in addition the cortical auditory evoked potential and the peripheral, brain-stem and cortical components of the somatosensory evoked potentials. Each of these evoked potentials remained in the presence of 0.75 mmol/1 glucose in plasma. The persistence of the somatosensory cortical evoked potential was unexpected since two other groups have reported the disappearance of this potential during hypoglycemia. The types of neuronal activity which can still be recorded in severe hypoglycemia are probably generated by neuronal structures with lower metabolic demands such as axons and oligosynaptic pathways, surviving on the consumption of endogenous substrates with compensatory elevation of local cerebral blood flow. Keywords: evoked potentials - - auditory - - somatosensory --. brain-stem auditory pathway (BAP) - - hypoglycemia - - cortical EP
In a previous study (Deutsch et al. 1983) it was shown that the evoked potentials of the auditory nerve and brain-stem auditory pathway (BAP) could still be recorded during severe insulin-induced hypoglycemia. In order to examine the possible differential effects of severe hypoglycemia on the functional activity of an additional sensory pathway and on electrical activity generated at different levels of the nervous system, a further study was conducted in which the somatosensory and auditory evoked potentials (peripheral nerve, brain-stem and cortical components) and the EEG were recorded in cats in a state of severe insulin-induced hypoglycemia.
Methods
These experiments were performed on 16 adult cats. Following a period of fasting of about 18 h, the cats were anesthetized by intraperitoneal injection of 40 m g / k g pentobarbital. Cannulae were inserted into the trachea, a femoral vein and both femoral arteries (one artery for continuous monitoring of
J A preliminary report of this study was presented at the regional meeting of the International U n i o n of Physiological Sciences, Jerusalem, August, 1984. Supported in part by the Ministry of Science, Israel. 2 Please address all correspondence to: Prof. H. Sohmer, Dept. of Physiology, Hebrew University-Hadassah Medical School, POB 1172, Jerusalem 91010, Israel.
arterial blood pressure and the second for blood sampling). The EEG was recorded between 2 copper screws inserted into the fronto-parietal skull on either side of the midline. In the first 11 cats in this series the evoked potentials were elicited and recorded by means of a laboratory-assembled modular evoked response system. The somatosensory stimulus was a 50 /~sec, 2 / s e c electrical pulse delivered by needle electrodes to the fore paw. The intensity was adjusted to elicit fore paw movement. The early components (peripheral nerve and brain-stem) of the somatosensory evoked potentials (SEPs) were recorded as the potential difference between a scalp needle electrode and a second needle electrode in the shoulder ipsilateral to the stimulated limb, filtered (200-3000 Hz), averaged using a 10 msec window (40 /~sec/address) and displayed scalp positive up. The cortical SEP (CSEP) was recorded between the contralateral skull screw electrode and the ipsilateral shoulder needle electrode, filtered (0.2-40 Hz), averaged using a 100 msec window (390 ~sec/address) and displayed scalp positive up. The auditory stimulus was a click at intensity 60 dB above the threshold of normal h u m a n listeners, i.e., 60 dB HL. The early components of the auditory evoked potentials, that is, the auditory nerve-brain-stem evoked response (BAP) to 20/sec clicks was recorded using the same electrodes, filter bandpass, averager window and display as the SEP. The cortical auditory evoked potential (CAEP) to 2 / s e c clicks was recorded, filtered, averaged and displayed as the CSEP. The evoked potentials in the remaining 5 cats were elicited and recorded by means of a Neurolab 2000 (Microshev Ltd.,
0013-4649/85/$3.30 © 1985 Elsevier Scientific Publishers Ireland, Ltd.
162 Israel). A recording needle electrode was placed in the skin of the scalp overlying the contralateral somatosensory cortex and a second needle electrode was placed in the neck. The CSEP was elicited by 4 / s e c 50 ,~sec pulses and the recorded activity was filtered 30-3000 Hz and averaged with a 51 msec window. The SEP was filtered 30-3000 Hz or 200-3000 Hz and averaged using a 12.5 msec window. The BAP to 2 0 / s e c clicks was filtered (200-3000 Hz) ~/nd averaged (12.5 msec window). The C A E P to 2 / s e c clicks was filtered (3-40 Hz) and averaged (382 msec window). Blood glucose levels were determined every 30 rain using the glucose oxidase kit of Boehringer (Werner et al. 1970). Experimental procedure Following control recording (EEG and each of the EPs) and arterial blood sampling (for glucose determination), an initial dose of insulin was injected. Smaller additional doses were given every half hour. The total dosage ranged between 230 and 1600 I U / k g with an average of 490 I U / k g . Electrical records and blood samples were obtained at least every 30 min. In order to maintain the hypoglycemic state for long periods the cats were paralysed (gallamine) and artificially ventilated and were given infusions of dopamine when necessary to maintain mean arterial blood pressure greater than 100 m m Hg. Body temperature was maintained at 37-38°C. The peak latency and peak-to-peak amplitude of the following EPs were evaluated: the BAP wave at about 2.8 msec; CAEP the prominent vertex positive wave with a latency of about 18 msec; SEP - - the 5 - 6 msec wave (shown to be of brain-stem origin by Nakanishi et al. 1982); CSEP - - the vertex positive 10-12 msec wave, The average change in latency and amplitude of each of these waves between the control and final severe hypoglycemic state was calculated and a paired t test was used to determine whether these latency and amplitude changes were significant.
Results
The results of a typical experiment are shown in Figs. 1 and 2 (Neurolab 2000). It can be seen that the CAEP (Fig. 1) and CSEP (Fig. 2) could still be evoked in the presence of a blood glucose level of 0.6 mmol/1 (10.8 rag%). In the CSEP trace some of the SEPs can be seen as small waves which were actually studied with a 12.5 msec window. The final EP traces and glucose levels were obtained 334 rain after the initial insulin administration (total received 900 I U / k g ) ; the EEG became isoelectric 93 ¢ min after insulin administration: the experiment was continued for an additional 244 rain and the glucose level was below 1.66 m m o l / l (30 rag%) for 290 rain. The average results of all of the experiments were similar, The blood glucose level fell below 1.66 m m o l / I 45 rain on Blood Gtucose (rnrnel / II
ABR
3.3
Cortical
~
j
o.6
-
~ ] 1.6 #V 1 msec
~ . ] l 2 ~V 30 msec
Fig. 1. Auditory evoked potentials before (3.3 m m o l / I glucose) and during severe hypoglycemia (0,6 retool/l: 10.8 mg%). The auditory nerve and brain-stem evoked responses are shown on the left and the cortical response on the right. The stimulus is simultaneous with the beginning of the trace.
TABLE I Evoked potential parameter changes induced during severe hypoglycemia (average and standard deviation). Gluca~e let~els
Initial
mmol/I (rag%)
4.6 + 1.2 (83.4_+22.3)
Final 0.75_+ 0,26 (13.5 _+ 4.7)
Auditoty EP %,5 latency %,5 amplitude
BA P +4.8_+14.3 -10.5_+83.2
P NS NS
CA EP - 1 6 . 3 _+25.6 - 1 4 . 5 _+60.2
P < 0.05 NS
SEP --2.8_+ 9.2 - 15.7 _+81.3
P NS NS
CSEP - 2 . 6 _+25.0 - ] 6,8 _+64.1
P NS NS
Somatosensory EP %A latency %,5 amplitude
163
Peripheral
Brood
Cortical
Glucose ( ram01 I [ )
3.3
0.6
~.]81 I rnsec
~v
~_] ~ ~V l, rnsec
Fig. 2. Somatosensory evoked potentials before and during severe hypoglycemia in the same experiment shown in Fig. 1. Note the continued relatively unaltered presence of each of the evoked potentials during hypoglycemia. The stimulus is simultaneous with the beginning of the trace. average following the initial insulin administration. The EEG became isoelectric in each cat. This occurred at an average glucose level of 1 m m o l / l , 80 min after insulin administration and the experiment was continued for an additional average period of 134 min. The average post-insulin duration of the experiments was 214 min (range: 120-334 min). There were large variations from experiment to experiment in the direction and magnitude of the amplitude and latency changes of the various EP waves. These changes (Table I) were not statistically significant except for the latency decrease of the CAEP. In no case did any of the EPs become isoelectric even at the lowest glucose blood levels. Discussion
The results of this study have shown that during hypoglycemia (0.75 mmol/1), the only significant EP change is a small decrease in the latency of the cortical AEP. All other EPs (SEP and AEP) including peripheral nerve, brain-stem and cortical components were not altered. This resistance of the AEP was originally considered paradoxical since other studies had demonstrated high metabolic rates in auditory regions of the brain (highest levels of glucose utilization (Des Rosiers et al. 1974) and highest levels of regional cerebral blood flow (Reivich et al. 1969)). However, it is now understood that these signs of elevated metabolism were probably induced by the ambient noise of the laboratory environment (Kennedy et al. 1975). The persistence of the somatosensory cortical evoked potential was unexpected since two other groups have reported the disappearance of this potential during hypoglycemia. Brierley and his group (Brierley et al. 1971; Meldrum et al. 1971), in a study devoted mainly to the induced neuropathological structural changes, recorded the cortical SEP in monkeys. The average blood glucose levels and durations of the experiments were similar to those in this study. Nevertheless, Meldrum et al. (1971) report the occurrence of cortical SEP silence 14 min prior to the EEG silence. They reported microvacuolation and ischemic cell changes in the neocortex, hippocampi and stria-
tum in most of the animals studied. Agardh and Rosdn (1983), studying mainly the induced alterations in cerebral metabolism, recorded the cortical SEP in rats and reached blood glucose levels of 0.6 m m o l / l and this state was maintained for up to 60 min. They also reported that in all cases the cortical SEP disappeared before the EEG. In the same animal model it has been shown that such hypoglycemia is accompanied by severe perturbations of cerebral energy metabolism (Lewis et al. 1974a, b). This finding of the disappearance of a cortical EP before the EEG becomes silent contradicts the results of this and several other studies which have reported the disappearance of the EEG before the cortical evoked potentials (e.g., Meldrum and Brierley 1969: Shelburne et al. 1976; Colin et al. 1978). Thus, it is difficult to reconcile the results of this laboratory, showing that in cats there was no case in which the cortical SEP (or the cortical AEP and brain-stem SEP and AEP) became electrically silent even when continued for an average period of 134 rain following EEG silence, with the results of Meldrum et al. (1971) and Agardh and Ros6n (1983) who report its disappearance prior to that of the EFG during similar degrees and shorter durations of hypoglycemia. It would appear from our study that the sites and neuronal structures responsible for generating the evoked potentials studied are still capable of generating their evoked electrical activity in spite of the severely decreased content of glucose in arterial blood, in the presence of an isoelectric EEG and in spite of the reported irreversible neuronal damage (Brierley et al. 1971) and marked perturbation of energy state. The continued generation of these types of evoked electrical activity may be due to the fact that they are generated by axons with the involvement of a relatively small number of synapses. This may be facilitated by the observed compensatory elevation of local cerebral blood flow (as long as adequate systemic arterial blood pressure is maintained) (MacMillan et al. 1974; AbdulR a h m a n et al. 1980:Siesj6 et al. 1983). In addition, it has been shown that neurons may continue to function in spite of decreased glucose availability by consumption of other endogenous substrates such as most components of the citric acid cycle, amino acids (Norberg and Siesj5 1976) and finally phospholipids, leading perhaps to the structural neuronal damage reported (Agardh et al. 1981). In conclusion, the evoked activity which can still be recorded in severe insulin-induced hypoglycemia is probably generated by neuronal structures with lower metabolic dem a n d s such as axons and oligosynaptic pathways while the compensatory mechanisms of elevated blood flow and consumption of endogenous substrates are sufficient to ensure their continued function. Resume Maintenance des potentiels ~voqubs somatosensoriels et audittf~ au cours d'une hypoglyc~mie sky,re chez le chat
Dans une 6tude pr6c6dente il a 6t6 d6montr6 que durant une hypoglyc6mie s6v6re induite par l'insuline chez des rats et
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des chats (0,38 m m o l / l soit 6,8 rag% et respectivement 0,8 m m o l / l soit 14 mg%) avec EEG iso61ectrique il ne s'dtait pas produit de modifications de latence et d'amplitude des r6ponses evoqu6es auditives du tronc c6r~bral. Dans 1'6tude pr~sente sur le chat, les r6ponses 6voqu6es mentionnO,es ci-dessus ont 6t6 compl6t6es par l'enregistrement du potentiel evoqu6 auditif cortical el p6riph6rique, et des potentiels 6voquds somatosensoriels p6riphOriques, du tronc cdr6bral et du cortex. Chacun de ces potentiels 6voquds est demeur6 en pr6sence de 0,75 mmol/1 de glucose dans le plasma. La persistance des potentiels 6voquds somatosensoriels corticaux 6tait inattendue du fair que deux autres groupes avaient d6crit la disparition de ces potentiels durant l'hypoglyc6mie. Les types d'activit6 des cellules nerveuses pouvant Etre encore enregistr6s lors d'hypoglyc6mies s6v
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