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Alternative Hypothesis to Explain Reduced Fear

Posted by sampatz on 10 Sep 2014 at 18:45 GMT

Samuel Patz, PhD
Department of Radiology, Harvard Medical School & Brigham and Women’s Hospital, Boston, MA 02115

I would like to propose an alternative hypothesis to explain your results demonstrating that xenon can alter fear memories in a rat. Briefly, the mechanism you propose to explain your results is that xenon inhibits NMDA receptors involved in learning and memory. And this, in turn, inhibits the association of a fear memory with a current stimulus.

The explanation that I am proposing is based on direct experience breathing xenon. For the past 17 years, my lab has been developing methods to measure lung function using hyperpolarized 129Xe [1-4].

As part of earlier studies, I performed over a hundred breath-holds of xenon. All studies were conducted in accordance with IRB and FDA IND approved protocols and informed consent was obtained as a prerequisite for participation. The protocol required that all inhaled gas mixtures contain at least 21% oxygen and no more than 70% xenon. In addition, the estimated alveolar xenon concentration could be no more than 35%, which is well below the level (~70%) that induces anesthesia [5]. Healthy subjects were allowed to hold their breath for up to 40 seconds. No adverse events were observed. Further details about our protocol and what was measured to ensure subject safety are available elsewhere [2].

As I read your paper, I reflected on my own experience when breathing xenon. If I held my breath for more than approximately 30s, I would begin to experience what I believe are the beginning effects of anesthesia, i.e. a deep relaxation and perhaps some lightheadedness. Of course, as soon as I exhaled and started breathing again, these effects rapidly disappeared. And certainly the lightheadedness could simply be the result of holding my breath.

Except for the first time I inhaled xenon when I was apprehensive, I would describe my experience of breathing xenon as very pleasant. And this leads me to speculate that your rats, after breathing xenon immediately after being exposed to a stimulus associated with a fear memory, will now have a new very pleasant memory to associate with the stimulus. And I would further expect that the new current memory, if it involves a sensation of euphoria and relaxation similar to what I experienced, may supplant the prior fear memory in terms of the dominant memory upon which the rat responds to the stimulus. If the mechanism that is described in the paper is also operative, then the two mechanisms for erasing the importance of the fear memory would reinforce and complement each other.

It is important to note that your protocol for the rats was an inhalation of a 25% xenon gas mixture for a period of one hour following the stimulus whereas my protocol was a single inhalation of a gas mixture containing up to 70% xenon followed by a breath-hold lasting up to 40 seconds. It is therefore important to determine whether the xenon concentration in my brain during breath-hold of 40s was similar to that which would have been achieved for continuous exposure to 25% xenon for one hour. For continuous exposure to a constant alveolar xenon concentration CA, I assume the partial pressure of xenon in the brain would become equal to that in the lung and the xenon concentration in the brain would be: Cbrain = (lambda)(lambdatissue) CA, where lambda is the air-blood partition coefficient and lambda tissue is the blood-tissue partition coefficient. Using values from the literature [6], the partition coefficients for air-blood, blood-grey matter, blood-white matter and blood-myelin are 0.17, 0.79, 1.32 and 17 respectively.

For a 40s transient breath-hold, a standard perfusion limited model was used to calculate the xenon concentration in the brain. The value of blood flow through the lung was taken as 5L/minute = 0.083L/s. Values of the perfusion in grey matter, white matter and myelin were obtained from Peled et al. [6] and are 0.0133, 0.00355, and 0.0035 ml blood/ml tissue/second respectively. For the transient exposure to xenon, we assumed an initial alveolar xenon concentration of 35% that was depleted only due to pulmonary blood flow transporting xenon dissolved in the blood out of the lung. Fick’s Law was used to calculate the xenon uptake in the brain tissue. The xenon concentration as a function of time from the transient breath-hold was normalized by the estimated concentration after continuous exposure to 25% [Xe]. After 40 seconds, the grey matter, white matter and myelin xenon concentrations are 16%, 2.7% and 0.21% of that predicted for continuous exposure to 25% alveolar xenon.

Based on this simple model, it is clear that the rats will have greater xenon concentration than I did in my 40 second breath-holds. And secondly, the exposure time of the rats is 3600 seconds compared to 40 seconds during my transient breath-hold. The rats were therefore exposed to xenon for a time that was 90 times longer and to much higher concentrations of xenon! Thus I would conclude that since I had a pleasurable experience from my exposure, it is very likely the rats had a more intense experience.

Literature Cited:
1. Butler JP, Mair RW, Hoffmann D, Hrovat MI, Rogers RA, Topulos GP, Walsworth RL, Patz S.
Measuring surface-area-to-volume ratios in soft porous materials using laser-polarized xenon interphase exchange NMR. J Physics: Condensed Matter, 14, L297-L304 (2002), PMID: 12741395.
2. Patz S, Hersman FW, Muradian I, Hrovat MI, Ruset IC, Ketel S, Jacobson F, Topulos GP, Hatabu H, Butler JP. Hyperpolarized 129Xe MRI: A Viable Functional Lung Imaging Modality?, European Journal of Radiology, 64 (2007) 334-344, PMID: 17890035.
3. Patz S, Muradian I, Hrovat MI, Ruset IC, Topulos GP, Covrig SD, Frederick E, Hatabu H, Hersman FW, Butler, JP. Human Pulmonary Imaging and Spectroscopy with Hyperpolarized 129Xe at 0.2T. Academic Radiology, 2008 Jun;15(6):713-27, PMID: 18486008.
4. Patz S, Muradyan I, Hrovat MI, Dabaghyan M, Washko GR, Hatabu H, Butler JP. Diffusion of Hyperpolarized 129Xe in the Lung: Simplified Model of 129Xe Septal Uptake & Experimental Results. New J Physics, 13 (2011) 015009, doi:10.1088/1367-2630/13/1/015009
5. Latchaw RE, Yonas H, Pentheny SL, Gur D. CT cerebral blood flow determination. Radiology
1987;163:251–4.
6. Peled S, Jolesz FA, Tsent C-H, Nascimben L, Albert MS, Walsworth RL. Determinants of Tissue
Delivery for 129Xe Magnetic Resonance in Humans, Magn Reson Med 36:340-344(1996).

No competing interests declared.