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Cerebral Blood Flow and Oxygen Consumption in Cortical Spreading Depression

Authors:
Avraham Mayevsky at Bar Ilan University
Avraham Mayevsky
Harvey R. Weiss
Harvey R. Weiss
Harvey R. Weiss
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Abstract and Figures

We determined the effects of spreading depression on local cerebral O2 supply, oxygenation, and O2 consumption in the anesthetized rat. Spreading depression was induced by application of 0.5 M KCl to the frontal cortex. Regional cerebral blood flow was determined with [14C]iodoantipyrine and regional O2 extraction was determined microspectrophotometrically. The passage of the spreading depression wave was determined with a multiprobe assembly that recorded NADH redox state (surface fluorometry), extracellular K+ activity, and DC steady potential (surface minielectrodes). As the wave of spreading depression passed, there was an increase in extracellular K+ and a decrease in NADH. Cerebral blood flow was significantly increased (120 +/- 51 ml/min/100 g, mean +/- SD) during the wave as compared with other regions. In the affected cortex, blood flow was not different from that in the contralateral cortex (69 +/- 28 ml/min/100 g) either before or after the wave of spreading depression passed. Arterial and venous O2 saturation were unaffected by the wave and the histogram of O2 saturations of examined veins followed a similar normal distribution in all regions. Oxygen extraction was not altered by the wave of spreading depression. Oxygen consumption was significantly increased during the wave to 7.4 +/- 3.7 ml O2/min/100 g compared with the contralateral cortex (5.1 +/- 2.6 ml/min/100 g) and other regions. It can be concluded that spreading depression caused an increase in cerebral O2 consumption that was adequately matched by an increase in local blood flow. Oxygen delivery was not limited during spreading depression and its effects were quickly over as evidenced by the lack of alteration in oxygenation after the wave of spreading depression passed.
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
         
     
       
 
    
         
          
       
       
  
      

      
     
 
       
      
     
  
       
       
         
  
      
         
  
      
        
       
     

  
       
        
       
       
        
 
        
   
       
 
    
        
      
    

      
         
      
   
   
    

 
     
       
      
       

         
    
      
    
  
     
      
       
  
       
       
      
      

  
 
       
       
       
       
 
  
      
     
      
      
    
    
  
     
     
    
     
      
     
  
       

        
      



       

      
     
     
  
       
     
   

  
       
    
      

       
      
      
      

      
       


        
 
         
      

  
        
    
       
   
        
         
    
       
       
     
        
        
    
        
 
  
   
    
        
  
  
          
  
  


       
         
 
      
       
 
      
       
    
        
     
       
            
   
  
  
      
        
      
         
      
       
         
   
       
 
      
      
     

  
    
        
   
    
  
  =        
     
        
     
 
 
 
        
       
       
       
    
     
      
     

     
   
        
      
       
          

   
  


       
 
        
 
    
         
       
 
   
        
  
       
        
    
       
    
       
 
       
 
  
 

      
       
        
     
        
        
   

 
  
      
        
     
       
  
 
   
     
     
       

       
 
       
      
        
         
  
      
        
 
 

 
  
     

       
 
     
      
       
      
   
   
   
         

    
 
  

   
    


  

  

  
 
        
       
        
      
    
      
       
 
    
         
       
     
     
       
   
    
         
        
      
 
       
      
  
   
         
     
         
      
          
       
  l 
   
     
 




      
     
          
      
    
 
   
        
   
      
      
  
  
       

      
   
 
 
  
 


e 
 
 
  
  
  
  
  
  
  
  
      
 e'   
     
          
          
  
    
       
       
       
      
      
    
        
  
         
       
        
     
   
       
      
  
     
  �     
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  
        
        
        
        
      
       
      
       
       
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  
       
 
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   
                    
                 

       
      
  
      
       
    
      
      
 
       

      
        
       
   

    
       
        
      
       

      
      
  
 
 
        
      
   
        
         
     
       
      
      
  

     
    
     
      
 
        
      
      
  
       
   
  
        
     
  
      
        
      
       
     
       
 
      
         
      
     
 
        
      
      
 
         
      
       
    
      
  
        
       
   
        
    
    
    
         
    
      
       
       
      

       

    
       
       
     
      
        
        
   
      
      
� 
        
        
       
        
       
 


       
      
      
  
      
      
  
        
        
        
         
       
       

       
 
 
   
      
      
      
     
       
     
      

       
       
      
       
   
       
     
    
      
    
     
      
      
        
  
     

     
    
     
    
  
 
 
       
  
      
        
      
    

    
  
     

        
      
   
    
   
  
       
 
          
    
  
      
   
     
       
        


   
      
        
   
 
        
       
  

     

     
   
        
       
       
        
     

       
  
       
   
        
  
    
    

  
  
         
  
       
  
    
       
    
 
    
  
      
     
     
    
  
  
 
      
      
       

        
      
   
    
        
  
         
        
      

        
 
    
   
       
   
  
    
      
   
    
         
     
     
          
      

         
      

        
     
       
      
      
 
  
      
  
... A CSD wave is usually accompanied by a transient increase in regional cortical blood flow (rCBF) (Mayevsky and Weiss, 1991). We measured the CSD-related changes in rCBF in both cortical areas (see Fig. 2) during the control phase when only ACSF was applied during all CSDs, and set the mean values as 100%. ...
Cortical spreading depolarization is a potential target for rat brain excitability modulation by Galanin
Article
Full-text available
  • Oct 2023
  • EXP NEUROL
The inhibitory neuropeptide Galanin (Gal) has been shown to mediate anticonvulsion and neuroprotection. Here we investigated whether Gal affects cortical spreading depolarization (CSD). CSD is considered the pathophysiological neuronal mechanism of migraine aura, and a neuronal mechanism aggravating brain damage upon afflictions of the brain. Immunohistochemistry localized Gal and the Gal receptors 1–3 (GalR1–3) in native rat cortex and evaluated microglial morphology after exposure to Gal. In anesthetized rats, Gal was applied alone and together with the GalR antagonists M40, M871, or SNAP 37889 locally to the exposed cortex. The spontaneous electrocorticogram and CSDs evoked by remote KCl pressure microinjection were measured. In rat cortex, Gal was present in all neurons of all cortical layers, but not in astrocytes, microglia and vessels. GalR2 and GalR3 were expressed throughout all neurons, whereas GalR1 was preponderantly located at neurons in layers IV and V, but only in about half of the neurons. In susceptible rats, topical application of Gal on cortex decreased CSD amplitude, slowed CSD propagation velocity, and increased the threshold for KCl to ignite CSD. In some rats, washout of previously applied Gal induced periods of epileptiform patterns in the electrocorticogram. Blockade of GalR2 by M871 robustly prevented all Gal effects on CSD, whereas blockade of GalR1 or GalR3 was less effective. Although microglia did not express GalRs, topical application of Gal changed microglial morphology indicating microglial activation. This effect of Gal on microglia was prevented by blocking neuronal GalR2. In conclusion, Gal has the potential to ameliorate CSD thus reducing pathophysiological neuronal events caused by or associated with CSD.
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Interaction Between Carbon Monoxide(CO) and Hyperbaric Oxygenation
Chapter
  • Jan 2024
Understanding of the mechanisms behind carbon monoxide intoxication and brain functions in vivo has a significant value in optimizing the therapeutic approach in patients (Thom and Keim, J Toxicol Clin Toxicol 27:141–156, 1989). A multiparametric monitoring assembly (MPA) connected to the brain of unanesthetized rats (Mayevsky et al. SPIE 1431:303–313, 1991) was used to assess the toxic effects of CO on various brain functions. Energy metabolism was evaluated by optical monitoring of relative CBF (using Laser Doppler flowmeter) and intramitochondrial redox state (using NADH surface fluorometry). Ionic homeostasis was assessed by measurements of K+, Ca2+, and H+ Levels in the extracellular space (using surface mini electrodes). The electrical parameters were ECoG and DC steady potential. Exposing the awake rat to 1000 ppm CO (40 min) followed by 3000 ppm (20 min) led to an increase in CBF followed by the development of brain depolarization characterized by changes in ionic homeostasis similar to those recorded under cortical spreading depression. Exposing the CO-intoxicated brain to external stimulation (KCl solution) led to metabolic and hemodynamic responses typical to an ischemic brain, namely, that due to limited O2 delivery to the cells, the increase in energy demand led to a decrease in CBF and an increase in NADH redox state. Also in most animals tested, oscillations in CBF and NADH redסx state were recorded after exposure to 3000 ppm CO as described in the ischemic brain (Mayevsky and Ziv Neurol Res 13:39–47, 1991). Therefore, we tried to improve brain oxygenation and interfere with the development of CO intoxication by exposing rats to 1–3 ATA 24 h before (Thom, Toxicol Appl Pharmacol 105:340–344, 1990a) as well as immediately after CO exposure. The results also indicated that suppression of brain energy metabolism is a characteristic manifestation of CO poisoning in rats. Restoration of cerebral energy metabolism by adequate dosage of HBO2 may become an important factor for recovery of brain activities after CO poisoning.
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Isoflurane lowers the cerebral metabolic rate of oxygen and prevents hypoxia during cortical spreading depolarization in vitro : An integrative experimental and modeling study
Article
  • Dec 2023
Cortical spreading depolarization (SD) imposes a massive increase in energy demand and therefore evolves as a target for treatment following acute brain injuries. Anesthetics are empirically used to reduce energy metabolism in critical brain conditions, yet their effect on metabolism during SD remains largely unknown. We investigated oxidative metabolism during SD in brain slices from Wistar rats. Extracellular potassium ([K ⁺ ] o ), local field potential and partial tissue oxygen pressure (p ti O 2 ) were measured simultaneously. The cerebral metabolic rate of oxygen (CMRO 2 ) was calculated using a reaction-diffusion model. By that, we tested the effect of clinically relevant concentrations of isoflurane on CMRO 2 during SD and modeled tissue oxygenation for different capillary pO 2 values. During SD, CMRO 2 increased 2.7-fold, resulting in transient hypoxia in the slice core. Isoflurane decreased CMRO 2 , reduced peak [K ⁺ ] o , and prolonged [K ⁺ ] o clearance, which indicates reduced synaptic transmission and sodium-potassium ATPase inhibition. Modeling tissue oxygenation during SD illustrates the need for increased capillary pO 2 levels to prevent hypoxia. In the absence thereof, isoflurane could improve tissue oxygenation by lowering CMRO 2 . Therefore, isoflurane is a promising candidate for pre-clinical studies on neuronal survival in conditions involving SD.
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Spontaneous Development of CSD Related to Brain Pathophysiological Conditions
Chapter
  • Oct 2022
In the current chapter, we will present the various pathophysiological that have the potential to induce CSD-like response. The mechanism of coupling between the availability of oxygen and the development of CSD may involve the leakage of potassium from the intracellular to the extracellular compartment in the cerebral cortex tissue. The interaction between the level of carbon dioxide in the breathing mixture in the hyperbaric chamber will be demonstrated. Also, the effects of various pharmacological agents on the development of CSD will be presented and discussed.KeywordsCSD and oxygen availabilityHyperoxiaIschemiaHypoxiaHyperbaric hyperoxiaAnoxia
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Discussion and Conclusions
Chapter
  • Oct 2022
A short summary of the main subjects described in this book is presented. This book is devoted to the metabolic aspects of the phenomenon cortical spreading depression (CSD) discovered in the early 1940s. The main differences between in vitro and in vivo conditions methodology adopted in both situations are discussed. The mitochondrial metabolic states described by Chance and Williams 1955 are compared to the in vivo conditions. Also, the use of NADH fluorescence together with other physiological parameters in patients is discussed.KeywordsIn vivo monitoringCortical spreading depressionMetabolic statePatients monitoringBrain mitochondrial function
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Sequence of Physiological Responses Recorded During Induced CSD Event
Chapter
  • Oct 2022
Since cortical spreading depression—CSD—is an event that led to increase in oxygen consumption, it was necessary to identify the mechanism behind the increase of oxygen supply to the mitochondria. The possible two options were tested, and from the results presented in this chapter, it was concluded that the extra oxygen needed for the recovery from the CSD wave was provided to the brain by the doubling of the CBF and not by downloading of oxygen from the oxygenated blood provided to the brain. This finding was the first and the sole direct proof of the very significant and important mechanism that regulates oxygen supply to the brain.KeywordsMultiparametric responses to CSDOxygen consumption during CSDHemoglobin oxygenation in CSDSequence of responses during CSDCBF changes in CSD
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Effects of Pharmacological Agents on CSD
Chapter
  • Oct 2022
The involvement of various drugs and pharmacological agents in the event named CSD is the subject of the current chapter. The advantage of using the multiparametric monitoring system as well as the multisite recoding of mitochondrial function and other brain activities during CSD is very clear. We are presenting the effects of three pharmacological agents, namely, carbon monoxide, nitric oxide, and alcohol on the CSD event.KeywordsCarbon monoxide (CO)Nitric oxide (NO)Alcohol effectsL-NAME inhibitionMultisite monitoringMultiparametric monitoring
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The Effects of Brain Metabolic and Other Perturbations on the Responses to Induced CSD
Chapter
  • Oct 2022
In this chapter, we will test the effects of various metabolic perturbations on the responses to CSD induced by exposing the brain to solution of high level of potassium. The metabolic perturbations included oxygen availability (mild hypoxia, hyperoxia, and partial ischemia) hypothermia, anesthesia, and the age of the rats. In the studies described in this chapter, we used the multiparametric monitoring systems as well as multisite system measuring mitochondrial function and electrical activity of the brain in 4 locations.KeywordsNormobaric hyperoxiaPartial IschemiaAnesthesiaHypothermiaAging ratsInduced CSD
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Clinical Monitoring of Cortical Spreading Depression (CSD) in the Human Brain
Chapter
  • Oct 2022
The technologies for monitoring of NADH and other parameters developed for animal study of CSD was applied to monitor patients that were exposed to various surgical procedures including long-term monitoring in the ICU. The brain was the main organ monitored in neurosurgical patients who underwent vascular procedures or treated in the ICU. Our studies led to the first discovery of the responses to CSD in neurosurgical patient in the ICU. Special devices and optical probes were developed and used in the early stage and were approved for use by the Institutional Review Board of the hospitals. Also, our devices were cleared by the FDA. Typical results of the main reports are presented in this chapter.KeywordsPatient monitoringHuman brain activityNADH monitoring in patientsPatients in neurosurgical ICU
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Cerebral Hemodynamics during Cortical Spreading Depression at different states of brain oxygenation and ventilation
Conference Paper
  • Jan 2002
We measure cerebral blood flow, blood oxygen saturation and volume during KCl induced cortical spreading depression in rat brain. Changes in peak duration, peak-to-peak delay and spreading speed during normoxia, hypoxia, hypercapnia and hypocapnia are quantified.
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Cortical spreading depression as a putative migraine mechanism
Article
  • Jan 1987
  • TRENDS NEUROSCI
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Persistent oligemia of rat cerebral cortex in the wake of spreading depression
Article
  • Nov 1982
Cerebral blood flow during and after spreading depression (SD) was studied in rat brain by quantitative autoradiography. The rise of cortical blood flow during SD was followed by 20 to 25
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Insulin effects on monovalent cation transport and Na-K-ATPase activity
Article
  • Apr 1978
  • Am J Physiol
The effects of insulin on monovalent cation transport and on Na-K-ATPase activity from intact cells, tissue homogenates, and purified enzyme of the avian salt gland were studied. Monovalent cation active transport, measured by ouabain-inhibitable 86Rb+ uptake, was significantly increased (21.9 +/- 7.3% SE) in tissue slices exposed to insulin (100 mU/ml) for 15 min. A small but significant (12.2 +/- 1.9%) increase in Na-K-ATPase activity was similarly observed after salt gland tissue slices were exposed to insulin. This increase in enzymatic activity did not occur when broken-cell homogenates were exposed to insulin. Purified preparations of Na-K-ATPase showed no insulin enhancement of activity either in the presence of optimal or less than fully activating Na+ and ATP concentrations. Na-K-ATPase activity was the same in detergent-activated homogenates of both control and insulin-treated slices, consistent with insulin activation of existing enzyme sites. These data support the hypothesis that at least part of the increase in monovalent cation active transport produced by insulin is related to enhanced Na-K-ATPase activity and indicate that the latter phenomenon is dependent on some components or properties of the intact cell.
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Metabolic responses of the awake cerebral cortex to anoxia hypoxia spreading depression and epileptiform activity
Article
  • Dec 1975
  • BRAIN RES
Using the time sharing fluorometer/reflectometer the measurement of NADH fluorescence as well as the reflected light was obtained from the surface of the awake rat brain cortex. The light was transferred to and from the brain via a flexible light pipe (made of quartz fibers) connected to a cannula implanted permanently above the brain. Exposing the rat to pure nitrogen atmosphere increased the fluorescence (reduction of NADH) by 32.3 +/- 6.1% in comparison to the normoxic fluorescence level. During cortical spreading depression (SD) the NADH fluorescence decreased (oxidation of NADH) by 17.3 +/- 2.8%. Exposing the rat to nitrogen after SD was elicited blocked the oxidation cycle observed during SD. Exposing the awake ras to 10, 7.5 or 5% O2 did not block the response of the brain to spreading depression or to Metrazol applied locally to the cortex. Under hypoxic conditions the brain showed a typical response to SD, namely, an oxidation cycle of NADH except that the duration of the cycle was longer and the decrease in the NADH level was smaller. The EEG activity recovered to normal even under 5%. The same effect of hypoxia was found when Metrazol was applied and epileptic activity was developed.
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