How to Become Smarter (69 page)

Serotonin plays a role in the regulation of mood, and pharmacological agents that increase the extracellular level of cerebral serotonin (SSRIs) are a standard of care for clinical depression in English-speaking countries [
714
]. Although SSRIs elevate the extracellular level of serotonin in the brain within 30 minutes, their therapeutic effect on mood usually manifests itself only after 2-3 weeks of daily administration; that is, SSRIs are long-acting pharmacological agents [
463
]. A legitimate question may arise whether exposure to cold can worsen mood or exacerbate symptoms of depression, since cooling can temporarily reduce serotonin content of the brain [
679
,
680
]. The answer is “no” because the role of serotonin in depression is complicated [
463
] and, paradoxically, a pharmacological agent that has the opposite effect to that of SSRIs, the selective serotonin reuptake
enhancer
tianeptine (brand names
Coaxil®
and
Stablon®
) also works as an effective antidepressant [
456
]. Tianeptine reduces the extracellular level of serotonin in the brain by promoting its absorption by neurons; SSRIs do the opposite. Both SSRIs and tianeptine are more effective than a placebo in clinical trials with depressed patients [
456
]. The FDA has not yet approved tianeptine in the United States, but government regulators in France, Spain, Germany, Brazil, India, and Eastern Europe have given it a green light many years ago [
456
,
715
]. It is possible that the effects of body cooling on mood are similar to the effects of tianeptine because both treatments reduce the level of serotonin in the brain.

There is a subtle difference between the effects of these treatments: systemic exposure to cold reduces the
total
level of serotonin in the brain (the sum of extracellular and intracellular serotonin [
679
,
680
]), whereas tianeptine reduces the extracellular level of serotonin [
716
] and its effect on total cerebral serotonin is unknown.

Body cooling can also affect dopamine circuits in some regions of the brain [
472
]. One experiment on rats has shown that exposure to cold increases the synthesis of dopamine in the striatum by about 50% [
472
]. Although it is not known precisely which parts of the striatum are affected by exposure to cold [
472
], an increased level of dopamine in the ventral part of the striatum (nucleus accumbens and olfactory tubercle) underlies the immediate euphoric effect (within 30 minutes) of dopamine reuptake inhibitors such as cocaine and amphetamine (the latter is also a dopamine-releasing agent and a norepinephrine reuptake inhibitor) [
458
,
459
]. But these treatments have different effects on the striatum. On the one hand, the dopaminergic drugs shift intracellular dopamine to the extracellular space, which can cause subsequent depletion of intracellular dopamine stores (at high doses of the drugs) [
658
]. On the other hand, exposure to cold increases the synthesis of dopamine [
472
], which will not result in dopamine depletion. One can usually interpret increased synthesis of dopamine as an elevated discharge rate of the dopaminergic neurons projecting to the brain region in question [
329
].

Several other experiments have shown that exposure to cold can increase activity of noradrenergic neurons of the locus ceruleus [
659
,
686
,
687
], a brain region whose main function is control of the sleep/wake cycle and regulation of the level of arousal [
717
], although it may also participate in the regulation of mood [
718
,
719
]. The activation of the locus ceruleus neurons may explain increased alertness during exposure to cold [
343
,
361
,
362
], since electrical stimulation of this brain region disrupts sleep [
720
].

The physiological effect of systemic cooling on the brain norepinephrine system is in some ways different and in some ways similar to the effect of noradrenergic antidepressant drugs (such as tricyclics and norepinephrine reuptake inhibitors, such as reboxetine [
721
]). Although cooling increases firing activity of noradrenergic neurons [
659
,
686
,
687
] (most of which originate in the locus ceruleus [
721
]), the above drugs typically
reduce
the discharge rate of these neurons. This is because these pharmacological agents increase extracellular concentration of norepinephrine and this suppresses the activity of noradrenergic neurons via inhibitory presynaptic receptors (feedback inhibition mechanism) [
721
]. The similarity of cooling and noradrenergic drugs may be that both treatments will enhance postsynaptic currents at the site of projection of a noradrenergic neuron: the former will do so by increasing the firing rate of this neuron whereas the latter by increasing the extracellular (synaptic) concentration of norepinephrine, which will increase stimulation of postsynaptic adrenergic receptors [
721
].

Modulation of the dopamine and norepinephrine systems by exposure to moderate cold in some ways resembles the effects of dopamine-norepinephrine reuptake inhibitors such as the atypical antidepressant bupropion (brand name
Wellbutrin®
) and some psychostimulants: amphetamine, methylphenidate, and modafinil [
722
,
723
]. Psychostimulants are short-acting agents, i.e. they have a rapid mood-lifting effect (within 30-60 minutes) [
332
,
458
] and amphetamine, in particular, used to be a widely prescribed antidepressant in the United States 40 years ago [
17
]. Clinical evidence does not support the effectiveness of most other psychostimulants for the treatment of depression [
390
]. It is worth mentioning that some psychostimulants exhibit euphoriant effects; that is, they can lift normal mood. This effect is not the same as the antidepressant effect (improvement of depressed mood) and a recent review showed that clinical trials of amphetamine and similar stimulants in patients with depression yielded mixed results regarding their effectiveness as antidepressants [
390
].

Another possible explanation for why cold water treatments may improve mood is because there is a high density of cold receptors in the skin (3-10 times greater than that of thermoreceptors that register warmth [
724
]). A whole body cold shower may serve as a mild electroshock for the brain because the sensory cortex will be flooded by numerous electrical impulses coming in from the peripheral cold receptors [
372
]. Sudden immersion in cold water is highly stressful [
357
]. Electrical stimulation of the brain forms the basis of several treatments for depression [
725
]. Electroshock therapy is a highly reliable antidepressant treatment. Psychiatrists usually prescribe it as a treatment of last resort when a patient fails to respond to other treatments [
726
]. There are other treatments based on electric devices: deep brain stimulation, vagus nerve stimulation, and cranial electrotherapy stimulation, which have shown efficacy in some clinical trials with depressed patients [
725
]. This mechanistic similarity of electric stimulation on the one hand and simultaneous stimulation of numerous thermoreceptors by cold water on the other, is another possible mechanism of the mood-altering effect of systemic cooling [
372
].

In summary, the similarity of the physiological effects of exposure to cold with those of some antidepressant treatments suggests that moderately cold hydrotherapy may be beneficial for depressed patients and further research in this area is needed [
372
]. Since many classes of antidepressant drugs are also beneficial in anxiety disorders (tricyclics, MAOIs, SSRIs, SNRIs) [
448
,
450
], cold hydrotherapy is likely to have antianxiety properties as well. The mechanism of the beneficial effects of antidepressant drugs in anxiety disorders is unknown at the time of this writing. A recent study out of Poland showed that cryotherapy (brief cooling in a chamber with extremely cold air) can benefit patients with some anxiety disorders [
376
]. Several studies have reported that the antidepressant tianeptine (which can lift normal mood [
392
] and has mild stimulant effects [
391
], similar to cooling) can reduce anxiety [
649
,
650
]. On the other hand, placebo rates are unusually high (up to 50%) in clinical trials with patients with anxiety [
470
,
471
], which may be responsible for the reported anxiolytic effects of some antidepressant drugs.

Rationale for the adapted cold shower procedure.
It may be more practical to use cold water instead of cold air for body cooling because thermal conductance of water is some 30 times greater than that of air [
420
]. For example, water of 20°C feels cold to the skin and has a significant cooling effect [
727
], whereas the air of the same temperature feels thermoneutral and has little or no cooling effect. Because water cools much more rapidly, cold-water treatments are much more stressful than cold air treatments [
357
,
388
], and therefore a gradual adaptation phase is necessary to make cold hydrotherapy less shocking.

A recent theoretical paper [
728
] proposed a possible unstressful procedure that can cool the skin rapidly, the adapted cold shower, and the text below outlines the procedure briefly. It is not the only possible cooling method, and this procedure was designed to be minimally stressful and to carry little or no risk of hypothermia [
728
]. One can use the adapted cold shower as follows: water temperature is 20°C, at a constant flow rate selected from the range 16 to 24 L/min, lasting 3 minutes; the whole-body shower follows a 5-minute gradual adaptation phase (expansion of the area of contact with cold water from the feet up, to make the cold shower less shocking). Addition of a thermoneutral (tepid) shower, 3-5 minutes, before the adapted cold shower can make the procedure even less stressful. A person can do the whole procedure twice a day (morning and afternoon, no later than 7 p.m.). Water of colder temperature is also an option (water at 16°C will not normally cause hypothermia [
378
]) and should have a stronger analgesic effect due to stronger stimulation of cutaneous thermoreceptors [
729
]. But this change may also make the procedure less comfortable.

An alternative approach can be gradual immersion in cold water at 20°C up to the neck [
394
]. The gradual lowering of a participant into the water can last 3 to 5 minutes to make the procedure less stressful and then the participant can stay immersed (up to the neck) in cold water for 3 minutes. The difference with adapted cold showers is that the cold-water immersion protocol may be more expensive to implement. Another difference is that cold water immersion at 20°C will lower both blood pressure and heart rate (due to the diving reflex [
730
]), whereas cold showers at 20°C will increase blood pressure slightly and lower heart rate (due to vasoconstriction and baroreflex [
377
,
731
]) temporarily. Immersion in colder water (14°C) will increase both blood pressure and heart rate and will also cause mild hypothermia [
386
,
730
]. Water will start to cause pain in the skin at 14°C and lower because this is the pain threshold of cold water [
417
,
418
]. All these effects are transient and will normally disappear as soon as the body cooling procedure is stopped [
386
,
397
,
730
].

Finally, immersion in 16-23°C water cannot cause hypothermia in normal test subjects even if it lasts for several hours [
378
] and therefore a brief hydrotherapy session at this temperature will be safe for most people. Nevertheless, my personal experience suggests that adapted cold showers at 20°C can worsen coughing if this symptom is present. The mechanism of this undesirable effect is unknown. Therefore, if coughing is present a patient should avoid cold showers or use a modified procedure as described in the
seventh section
of Chapter Two.