i8^8 



HWDHOOK OF PHYSIOLOGY 



NEUROPHYSIOLOGY III 



degree of elevation of the ammonia level in the 



arteriaJ blood. In all the cases of hepatic failure, 

 whether coma was present or not, the blood ammonia 

 concentration was elevated. A similar correlation 

 between the Idood ammonia level and the occurrence 

 of coma following meat ingestion has been reported in 

 a patient with cirrhosis and an Eck fistula (126). 

 On the basis of these observations, Bessman & Bess- 

 man (14) have pustulated that hepatic coma and the 

 reduced metabolic rate associated with it result from 

 a slowing of the tricarboxylic cycle in the brain be- 

 cause of the diversion of a-ketoglutarate by reductive 

 animation, a process accelerated by the higher uptake 

 of ammonia by the brain in this disease. The product 

 of this reaction is glutamate, and these authors have 

 found an increase in the glutamate produced by the 

 brain in hepatic coma (13). This hypothesis, although 

 interesting and ingenious, is somewhat tenuous in 

 view of the findings of other investigators of a lack 

 of correlation between the degree of coma and the 

 arterial blood ammonia level (44, 189). Indeed, 

 coma has been observed in the absence of an increase 

 in the ammonia concentration of the blood (39, 44). 



Depression of both mental function and cerebral 

 metabolic rate has been observed in uremic coma 

 (73> '55)- The chemical basis of the functional and 

 metabolic disturbances in the brain in this condition 

 also remains undetermined. 



In the comatose states associated with these systemic 

 diseases, there is a depression of both metabolic rate 

 and cerebral function. From the available evidence, 

 it is impossible to state which, if either, is the primary 

 change. It is possible that the depressions of both 

 functions, although well correlated with each other, 

 ictually independent reflections of a more general 

 impairment of neuronal processes bv some unknown 

 I. M tors mi i< but lo die disease. 



ANESTHESIA. The stale of unconsciousness produced 

 b\ anesthetic agents is similarly associated with 

 111. nked depression of the cerebral metabolic rale. 

 Reductions in the cerebral oxygen consumption 

 comparable to those occurring in the comas of the 



metabolic diseases have been observed during 



iliiopeni.il anesthesia in man (83, 193), in the monkey 

 (162) and in the perfused cal brain (51). Recently 

 the steroid, 21 hydroxypregnane-3,20-dione sodium 



succinate, has been found to produce anesthesia in 

 man with the same depression in cerebral oxygen 

 consumption (61, 64). The reduced metabolic ran- 

 is the resull oi a depressed cerebral oxygen demand 

 and not ol a reduction in cerebral blood How or 



nutrient supply. Quastel 1 1 ;<)) has suggested thai 

 anesthetics act primarily by interference with the 

 intracellular oxidation of glucose. Bain (5) has found 

 in vitro that barbiturates depress oxidative phos- 

 phorylation. Either of these mechanisms would 

 decrease the availability of energy to the brain. The 

 results of studies of the intermediate metabolites 

 in the anesthetized brain are not compatible with 

 these mechanisms. During anesthesia there is a 

 reduction in the lactic acid and an increase in the 

 ATI' and phosphocreatine levels in the brain (141, 

 182, 183); the brain acetylcholine level is increased 

 and that of ammonia reduced (141— 143). These 

 changes, the opposite of those observed with increased 

 energy demand as, for example, in convulsions, are 

 indicative of a reduction in energy utilization rather 

 than of energy availability. They arc more com- 

 patible with the view suggested by the findings of 

 Larrabee and associates 1110, iu, 1131 that an- 

 esthetics act by blocking synaptic transmission, thus 

 reducing neuronal interaction and functional ac- 

 tivity and, consequentlv, metabolic demands. The 

 same mechanism has been postulated for the de- 

 pressed cerebral metabolic rate following lobotomy 

 in man ( 1 70). 



convulsive disorders. The metabolic consequences 



of the induction of convulsions have been discussed 

 above in the section on functional activity and 

 metabolism. The cerebral metabolic rate during 

 convulsive seizures has not vet been measured in 

 man. A series of electroconvulsive treatments, how- 

 ever, does not appear to cause any permanent altera- 

 tion of cerebral metabolic rate 1 1 <)(> ). In studies during 

 the interseizure period, (haul and associates il>->i 

 found a normal rate of cerebral oxygen consumption 

 in adult epileptic patients, but Kennedy (unpublished 

 observations) has found moderate reductions in 

 children with the same disease. Preliminary observa- 

 tions indicate that in those children who show signs 

 of deterioration or mental retardation, the reduction 



in cerebral metabolic rate is even greater (Kennedy, 

 unpublished obsen ations I. 



Some biochemical studies which suggest interrela- 

 tions between abnormalities of brain lissue metabo- 

 lism and convulsive activitv are of special interest. 

 In human cerebral cortical tissue excised from 

 epileptogenic foci, elevated cholinesterase activitv, 

 impaired production of •bound' acetylcholine and 

 abnormal metabolism of glutamic acid have been 

 described (184, if!''. 187) Hiese metabolic defects 



were reversed in vitTO bv the addition of ulutamine. 





