When people think about cryotherapy the first thing they think about is, perhaps, the effect on metabolism, muscle soreness, and recovery, athletic performance or just the more immediate effects on the body in general. What I find the most interesting, and maybe a bit more clear cut in some ways, are the effects on the brain. It’s also an area that just generally interests me more, so let’s talk about that first. There is anecdotal evidence that cold exposure improves mood and it has been suggested that cold showers may even be used to prevent and treat depression. Let’s take a quick dive into one of the mechanisms by which cold exposure may improve mood.

One of the most consistent and profound physiological responses to cold exposure is a robust release of norepinephrine into the bloodstream, as well as in the locus coeruleus region of the brain. What makes norepinephrine so interesting is that it’s not only a hormone but also a neurotransmitter and is involved in vigilance, focus, attention and mood. The cold induces this robust increase in norepinephrine in both mice and humans and is a response mediated by the sympathetic nervous system, the primary purpose of which is to stimulate the body’s fight ­or ­flight response.

Decreased norepinephrine neurotransmission is associated with
inattention, decreased focus and cognitive ability, low energy, and poor mood (generally). When norepinephrine is depleted in people by pharmacological intervention, it causes depression. In fact, both ADHD and depression are sometimes treated with norepinephrine reuptake inhibitors, which of course may come with its own set of drawbacks. Norepinephrine also acts as a hormone and, when released into the bloodstream, acutely increases vasoconstriction (which is the constriction of blood vessels). This last part, of course, helps to explain why norepinephrine plays a really important part in our response to cold: by increasing vasoconstriction, we decrease the total surface area by which the blood is able to lose heat to the environment.

Let’s talk about temperatures. Just how cold do you have to get in order to get that hit of norepinephrine? There does appear to be temperature threshold for activating the sympathetic nervous system. For example, cold­water immersion at 68°F (20°C) for 1 hour does not appear to activate norepinephrine release whereas 1 hour at 57°F (14°C) increased it by 530% and also increased dopamine by 250%. Personally, I think dopamine accompanies norepinephrine quite nicely.

Long durations, however, aren’t necessarily required for a potent release of norepinephrine. A long-term study in humans directly compared people that immersed themselves in cold water at 40°F (4.4°C) for 20 seconds to those that did whole body cryotherapy for 2 minutes at ­166°F (­110°C) three times a week for 12 weeks and found that in both cases, plasma norepinephrine increased 2 to 3­fold (200 to 300%) and this release of norepinephrine didn’t seem to be reduced with habituation to cold. Those levels did, however, drop over the course of an hour after the exposure.
On a side note, guess what else increases norepinephrine release? Heat, as well as lactate, the latter of which is produced by exercise. Learn more about lactate as a brain fuel with this video interview of renown exercise physiologist and pioneer of the lactate shuttle theory Dr. George Brooks… or… learn more about heat­induced norepinephrine release in my video on sauna use.

Finally, one last note about norepinephrine: it also has other profound effects on pain, metabolism, and inflammation. This last point, in particular, may be relevant to the dialogue surrounding mood since inflammation has the quality of being able to also inhibit serotonin release.
We will return to the topic of pain, metabolism, and inflammation in a moment, however. A cold shock protein in the brain. In previous articles and videos, I’ve talked ad nauseam about the benefits of heat shock proteins, and how they may even be involved in human longevity. Exposure to the other temperature extreme, cold, also triggers heat shock proteins… but in addition to that, there’s a class of proteins that are specific to the cold: cold shock proteins. Much of what we know about the physiological responses to cold come from research on hibernating mammals. Hibernation involves a profound metabolic shift that is driven by the fundamental biological need to conserve energy in the winter. When the body is cooled many genes are shut down, the exception, however, are genes involved in lipid metabolism (fat burning) and the group of proteins known as cold shock proteins. The expression of these two categories of genes are increased upon cold exposure.

One particular cold shock protein known as RNA binding motif 3 (RBM3) especially stands out for the purposes of our discussion. RBM3 is found in the brain, heart, liver, and skeletal muscle and increases in activity greatly upon even mild cold exposure.
Bringing lost synapses back from the brink. Synapses between neurons actually break down during cold exposure. Synapses are how neurons communicate with each other and how memories are formed. This interesting phenomenon was first observed from studies done on hibernating animals.
However, when animals that hibernate warm back up close to 100% of the synapses regenerate. That’s a pretty amazing feat! The best part is…this effect may not be limited to just hibernating animals. It’s also been shown in laboratory mice, which are not hibernating animals. Mice that were cooled using a special protocol that included a pharmacological way to dramatically lower body temperature in combination with cold air exposure at a temperature of 41°F (5°C) for 45 minutes experienced ~26% loss of synapses in the hippocampus, which is part of the brain responsible for learning and memory. Once these same mice were allowed to warm back up, they were able to rapidly regenerate around 93% of those synapses that were lost to the cold.

Here’s the exciting news: the mechanism by which the lost synapses regenerate was found to be dependent on boosting the activity of RBM3, a cold shock protein that is conserved in humans. We have it too! The reason RBM3 is necessary for this restoration of synapses is because of the role this cold shock protein plays in binding to RNA to increase protein synthesis at the dendrites, which are a
part of the neuron that communicates with synapses. This enables the RBM3 cold shock protein to regenerate those damaged neurons. A single exposure to this cold shock protocol at 41°F (5°C) for 45 minutes was enough to increase RBM3 in the brain for 3 days (in mice). When this procedure was repeated once a week for two weeks in a row, not only did it robustly increase the expression of RBM3 for those two weeks but also for an additional six weeks after that.

What if synapses could be brought back from insults other than the cold? This is where things get really interesting. Mice that were experimentally induced to have neurodegenerative disease from prion infection, when exposed to two rounds of the cold exposure procedure early in life, were protected against the loss of synapses, allowing them to have more than twice as many synapses (in the brain tissue sampled) as the mice that didn’t get the treatment 12 weeks after being infected. The experimental cold stress also prevented cognitive and behavioral deficits that would’ve normally occurred in these mice as they progressed into later stages of neurodegeneration. The cold shock they were exposed to increased the expression of the cold shock protein RBM3 for several weeks, and this delayed the neuronal defects that usually occurred in these mice.

It may be pretty obvious that the ability to prevent the loss of synapses is pretty significant and would have huge implications if such a thing could be demonstrated in humans! Losing synapses occur with normal brain aging and is accelerated in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease and also after traumatic brain injury. Obviously, there are some novel and very interesting mechanisms at play here and the ability to protect synapses effectively might have huge implications for Alzheimer’s disease, other neurodegenerative diseases, as well as brain aging in general. Let’s talk about the human relevance of cold shock proteins. This RBM3 stuff is all very new research and we don’t really know if this effect would occur in the same way in humans. The question is how much does core body temperature need to be lowered to activate RBM3? It appears that a 2°F reduction in core body temperature is enough to induce cold shock proteins, including RBM3, in human astrocytes (a type of brain cell). As an aside, adding some melatonin to the mix may also have an effect of enhancing RBM3 even more, and supplementing with it also has an effect of lowering core body temperature. Okay, but, to put that 2ºF in perspective: this is a very achievable dip in body temperature that qualifies as only a very mild hypothermia since anything below 96.8ºF is considered hypothermic.

By way of example, in one study, young men that stayed submerged in cold water of 68°F (20°C) for one hour were able to lower their rectal temperature to around 96.9°F (36.1°C) or if they stayed in 57.2ºF (14ºC) water for 1 hour they were able to lower their temperature to 96.1°F (35.6°C). This just goes to illustrate how attainable this level of cold shock is. The Effects of Cold Exposure on Inflammation and Immune Function The purpose of inflammation is to eliminate the initial cause of cell injury, clear out dead cells and tissues damaged from the original insult and the inflammatory process, and to initiate tissue repair.

However, when this process runs awry, in the absence of actual biological threat, we’re in trouble. Inflammation has been identified as the key driver of the aging process, and is associated with most age­related diseases. A recent study looked at a variety of biomarkers in old people (age 85­99), centenarians (100), semi supercentenarians (105+) and super­centenarians (110+) and found that low inflammation was the only biomarker that predicted survival and cognitive capabilities across ALL age groups.

Norepinephrine reduces inflammation. Earlier we focused mostly on the effects of norepinephrine in the context of its role as a neurotransmitter, but when studies show it can be increased by as much as 5­fold from extreme cold stress, it’s worth talking a little bit about some of its other roles. One of the roles norepinephrine may also play is in reducing inflammation. Norepinephrine inhibits the inflammatory pathway by decreasing tumor necrosis factor alpha (TNF­alpha), a very potent molecule that increases inflammation. An excess of the inflammatory cytokine TNF­alpha has been implicated in almost every human disease ranging from type 2 diabetes to inflammatory bowel disease to cancer. Believe me, too much of this stuff is bad. In addition to reducing TNF­alpha, norepinephrine has also been shown to decrease other nasty chemicals such as macrophage inflammatory protein­1α (MIP­1α), which is produced by immune cells and may play a role in rheumatoid arthritis. It’s important to note that these anti-inflammatory qualities of norepinephrine qualities of cold ­induced norepinephrine, while probably being beneficial in some contexts, may add some level of nuance or complexity to our discussion of the effects of cold modalities, such as winter swimming, Coldwater immersion, or cryotherapy in the context of athletic performance. We’ll get back to that in a moment, however.

Whole-body cryotherapy and arthritis. Reductions in systemic inflammation are, for the most part, usually unambiguously positive. One such example that stands out and where this might especially be the case is arthritis. In a randomized controlled trial patients with arthritis underwent whole-body cryotherapy ­166°F (­110°C) for 2­3 minutes three times a week for 1 week had a significant reduction in pain. There may be many mechanisms at play here including the cold ­induced reduction in inflammatory cytokines mentioned a moment ago.

Interestingly, in another study, local cryotherapy, in other words, cooling just the affected tissue, was shown to inhibit harmful collagenase activity on collagen, which is an enzyme that breaks down collagen, and it also decreased the production of inflammatory E2 series prostaglandins.

Some of the pain alleviating effects of cold exposure, particularly in the case of whole-body cryotherapy, may, in fact, be due to increased norepinephrine since inflammation itself causes pain. In fact, spinal injection of compounds that induce a release of norepinephrine has been shown to alleviate pain in human and animal studies.

Let’s talk brain inflammation and mood. Pro­inflammatory molecules (such as TNF­alpha and the E2 series prostaglandins) have been shown to cross the blood­brain barrier and activate the brain’s immune cells known as microglia. This is bad. It seems very possible that therapeutic strategies that increase norepinephrine, such as cold-water immersion and whole body cryotherapy, may be a good preventative measure which generally lowers inflammation and thus facilitates this preventative process of attenuating what is otherwise a major contributor to aging in general, but in this case, the brain in particular.

I’ve also discussed, in a previous publication, the fact that inflammatory molecules probably contribute to depression and anxiety by inhibiting the release of serotonin from neurons. This may be another implication of using cold shock to reduce neural inflammatory processes. Of course, more direct evidence needs to be shown to link cold shock as a strategy for the potential treatment of mood disorders, but it seems like an interesting and promising area of inquiry.

Let’s talk general immune function. All this talk of cold exposure, either from cold­ water immersion or cryotherapy, lowering inflammation may have you thinking that you might be better off with fewer immune cells since they seem to wreak so much havoc. Actually, having a large number of immune cells is generally a good thing, so long as they’re not unnecessarily active. I already mention how inflammation has been identified as a key driver of the aging process but I also want to point out that the immune system plays another important role in the aging process. Aging is associated with immunosenescence (non­functional immune cells) and a general reduction in immune cells. In fact, being very long lived or, making it to the age of a super­centenarian, is associated with having a healthier biological stock of immune cells. You want to have a good number of various types of immune cells, but you also want them to be quiet unless there is a good reason to be loud.

So how does the cold affect our “stock” of immune cells? It appears to increase them, at least certain types of immune cells. Long-term Coldwater immersion (3 times a week for 6 weeks) in healthy males was shown to increase lymphocyte numbers. This is in line with the fact that habitual winter swimmers have higher numbers of white blood cells compared to non­habitual winter swimmers. Additionally, another study demonstrated that cold exposure in a climatic chamber at 41°F (5°C) increased white blood cell numbers including cytotoxic T lymphocytes, which are a specialized type of immune cell that kills cancer cells. Males exposed to a cold (4°C) room for 30 minutes decreases their core body temperature by around 0.45°C and increased natural killer T cell number and activity. Natural T killer cells are another a type of immune cell that kill viruses and tumor cells.

All of this may serve to bolster the anecdote shared often among communities of winter swimmers, which is that they experience fewer everyday cold and flu symptoms. In fact, an association has been demonstrated in epidemiological studies between winter swimming and a 40% decreased incidence of respiratory tract infections. More work needs to be done to better understand what the long-term effects of chronic cold exposure are on immune cell numbers and functions to state definitively what this all means, though.