Cortical excitability and the partial pressure of [mostly endogenous] carbon dioxide

“Cortical excitability, here defined as the strength of the response of cortical neurons to a given stimulation, reflects neuron reactivity and response specificity and is therefore a fundamental aspect of human brain function.” Ly, J., Gaggioni, G., Chellappa, S. et al. Circadian regulation of human cortical excitability. Nat Commun 7, 11828 (2016). https://doi.org/10.1038/ncomms11828

SIGNIFICANCE STATEMENT “In this study, we show for the first time that neuronal oscillatory power is intimately linked to arterial CO₂ concentration down to the fine-scale modulations that occur during spontaneous breathing. We extend these results to demonstrate a correlation between neuronal oscillatory power and spontaneous arterial CO₂ fluctuations in awake humans at rest. This work identifies a need for studies investigating resting-state networks in the human brain to measure and account for the impact of spontaneous changes in arterial CO₂ on the neuronal signals of interest. Changes in breathing pattern that are time locked to task performance could also lead to confounding effects on neuronal oscillatory power when considering the electrophysiological response to functional stimulation”. Arterial CO₂ Fluctuations Modulate Neuronal Rhythmicity: Implications for MEG and fMRI Studies of Resting-State Networks Ian D. Driver, Joseph R. Whittaker, Molly G. Bright, Suresh D. Muthukumaraswamy and Kevin Murphy Journal of Neuroscience 17 August 2016,  36 (33) 8541-8550; DOI: https://doi.org/10.1523/JNEUROSCI.4263-15.2016

And……….

…………The strong effects of changes in PaCO2 on the cerebral vasculature, first discovered in 1928 by Forbes and Wolff via direct observation of the pial arteries through a glass window in animals, was subsequently confirmed in humans, first indirectly by Lennox and Gibbs in 1932 by means of jugular vein PO2 measurements, and then directly by Kety and Schmidt5 in 1946 using their whole-brain cerebral blood flow (CBF) technique that used inhaled N2O. These studies established that hypercapnia is the most potent brain vasodilator, and conversely hypocapnia a very potent vasoconstrictor. .…….The Harper and Glass 1965 article [‘Effect of alterations in the arterial carbon dioxide tension on the blood flow through the cerebral cortex at normal and low arterial blood pressures’, 1965 JNNP A Murray Harper and HI Glass was the first to assess the effects of changes in the arterial partial pressure of CO2 (PaCO2) on the cerebral circulation in conditions of normal arterial blood pressure, moderate hypotension and severe hypotension. …..These findings and others have led to major advances in understanding the disorders of the cerebral circulation involved in numerous neurological and neurosurgical conditions, and in turn has impacted to the present day the management of the afflicted patients.….for example these and other observations have major clinical implications in numerous medical disciplines, particularly neuroanaesthesia, neurointensive care and, of course, cerebrovascular diseases—specifically, that, on top of PaO2, both blood pressure and PaCO2 have to be closely monitored and controlled to avoid worsening of the already present brain damage. A MODERN 2020 CENTENARY PERSPECTIVE ON TRAIL BLAZING PAPERS FROM THE JNNP ARCHIVE The effect of changing arterial blood pressure and carbon dioxide on cerebral blood flow Jean Claude Baron…………..

” CO₂ serves as one of the fundamental regulators of cerebral blood flow (CBF).” HYPOTHESIS AND THEORY article Front. Physiol., 14 September 2012 | https://doi.org/10.3389/fphys.2012.00365 pCO₂ and pH regulation of cerebral blood flow SeongHun Yoon¹, Mario Zuccarello² and Robert M. Rapoport¹*

The human body is critically dependent on the ventilatory control system for adequate uptake of oxygen and removal of carbon dioxide (CO₂).  Potent opioid analgesics, through their actions on μ-opioid receptor (MOR) expressed on respiratory neurons in the brainstem, depress ventilation. Opioid-induced respiratory depression (OIRD) is potentially life threatening and the cause of substantial morbidity and mortality F1000Prime Rep. 2014; 6: 79. Published online 2014 Sep 4. doi: 10.12703/P6-79 Opioid-induced respiratory depression: reversal by non-opioid drugs Rutger van der Schier, Margot Roozekrans, Monique van Velzen, Albert Dahan, and  Marieke Niesters

 ” PaCO₂ is the most potent regulator of CBF,[cerebral blood flow] and even small fluctuations can result in large changes in CBF.” Compr Physiol . 2019 Jun 12;9(3):1101-1154. doi: 10.1002/cphy.c180021. Regulation of the Cerebral Circulation by Arterial Carbon Dioxide Ryan L Hoiland ¹, Joseph A Fisher ², Philip N Ainslie ¹

It has been known for a long time that hypercapnia has rather striking effects on the human central nervous system (Brown, 1930; Sieker & Hickam, 1956). Although a variable amount of excitation may be seen,the predominant effect is loss of consciousness. According to Brown(1930), most subjects cannot tolerate more than 10-12 % of C02 for longer than 2min. The mechanism and site of action of C02 have never been very clear.From early studies on the electrocorticogram…, (Bremer & Thomas, 1936), it seemed that the cortex was affected directly by C02, low doses exciting and large doses depressing the neurones. Although later publications in Russia (cf. Ivanov, 1962) have agreed with this interpreta- tion, some other authors (Gellhorn & French, 1953; Gellhorn, 1954; Dell & Bonvallet, 1954) have claimed that the brain stem is particularly sensitive to C02 and that cortical arousal is only secondary to activation of the mid-brain and hypothalamus. The sole direct action observed was a strong depression of the isolated cortex by large amounts of C02 (Gellhorn& French, 1953)…….. A recently developed method for the continuous recording of the cortical C02 tension(Pco,)(Siesj6,1961) has been combined in the present experiments with a technique for testing directly changes in the excitability of single neurones. It will be shown that even in the isolated cortex, many cells are affected by a small increase in Pco2, and that the resulting changes in excitability are rather complex, with evidence of both excitation and depression.... J Physiol. 1965 Jan; 176(1): 105–122. doi: 10.1113/jphysiol.1965.sp007538 Cortical CO₂ tension and neuronal excitability K. Krnjević, Mirjana Randić, and  B. K. Siesjö

By the way, in the case of Paula, these complex complex cortical neuronal changes, with evidence of both cortical excitation and cortical depression might explain her increased arousal in the form of high levels of anguish and distress [cortical excitement of neutrons] , AND her mental confusion and psychomotor retardation [cortical depression of neutrons], when her already baseline depressed rate of ventilation became inadequate, most likely due to cumulative neuromuscular weakness from physical illness [infection, inflammation, etc.resulting in a weakened state and poor body condition].

Dr Emile Kraepelin mentions respiratory depression and other abnormal ventilatory patterns in ‘Manic Depressive Insanity” and he does not do this lightly. Dr Kraepelin measured the respiratory rates and other vital signs [blood pressure, heart rate, and body temperature] and also measured the speed and quality of problem solving and thinking and knew the link between ventilatory failure and mental confusion.

And yet, even as many findings about cerebral blood flow, endogenous carbon dioxide,, and effects on cortical and other neurons have led to major advances in understanding the disorders of the cerebral circulation involved in numerous neurological and neurosurgical conditions, and in turn has impacted to the present day the management of the afflicted patients.….for example these and other observations have major clinical implications in numerous medical disciplines, particularly neuroanaesthesia, neurointensive care and, of course, cerebrovascular diseases—specifically, that, on top of PaO2, both blood pressure and PaCO2 have to be closely monitored and controlled, These and other observations have had no effect on medical protocols in the field of psychiatry.

Psychiatry remains ignorant of the importance of abnormal baseline respiratory rate, PC02, cerebral vasodilation, effect of depressed respiratory rate [no drugs, no yoga] and neuromuscular weakness on cerebral blood flow and intracranial pressure and the physical signs underlying the morbidity involved in the diagnosis and treatments of bipolar depression and bipolar mania [morbidity means disability, resulting from illness, in particular mental confusion and mood and motor impairment] .

It is time to bring psychiatry into the scientific world of brain function and its relationship with the production endogenous C02 and its control via the all too vulnerable skeletal muscle system.

Please share these ideas with clinical researchers …..to possibly expand their scientific and biochemical thinking on brain function, the external gases we breath and the internal gases we produce with cellular metabolism, the ability of our skeletal muscles to control our internal milieu , homeostasis and the function of Mind..

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