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A radical hypothesis on the nature of sleep
Journal Pre-proofs A radical hypothesis on the nature of sleep John C. Ashton PII: DOI: Reference:
S0306-9877(19)31039-4 https://doi.org/10.1016/j.mehy.2019.109433 YMEHY 109434
To appear in:
Medical Hypotheses
Received Date: Revised Date: Accepted Date:
14 September 2019 7 October 2019 10 October 2019
Please cite this article as: J.C. Ashton, A radical hypothesis on the nature of sleep, Medical Hypotheses (2019), doi: https://doi.org/10.1016/j.mehy.2019.109433
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Ltd.
For: Medical Hypotheses 31 July 2019
A radical hypothesis on the nature of sleep.
John C. Ashton Department of Pharmacology & Toxicology, Otago School of Biomedical Sciences, University of Otago, Dunedin, New Zealand. +6434793040 [email protected]
Running Head: False research findings.
Keywords: dexamethasone; proximate and ultimate mechanisms; sleep; wakefulness
Abstract Dexamethasone has been observed to cause night-time wakefulness without accompanying fatigue. It is proposed here that the drug interrupts a sleep signal, and that altough sleep has an ultimate ecological function, this signal is a proximate mechanism but not an ultimate physiological necessity, such that sleep is not a necessity.
Introduction The background to the proposed hypothesis is a medical event experienced by the author in early 2019. Discharged from hospital with secondary brain metastases, the author was prescribed alectinib for ALK-positive cancer, and dexamethasone to control brain oedema during the initial phases of alectinib treatment. The dose of dexamethasone started at 16 mg/day, tapered to 14mg/day at day 3, 12 mg/day at day 7, and then tapering by 2 mg/day increments week to hold at 4 mg/day, continued until MRI scan confirmed a strong tumour response to alectinib, at which point dexamethasone was tapered further to zero. In the time when the author was taking 4 mg/day dexamethasone, he barely slept. In the first week, complete wakefulness through the night was usual, and in subsequent weeks more than one hour of sleep a night unusual, but with progressively more sleep with dose reductions; though only to approximately 3 hours a night at 4 mg/day. Surprisingly, the author was not fatigued, and did not have the urge to sleep during the day. Importantly, although being told that dexamethasone causes insomnia, as he was practicing Acceptance and Commitment Therapy (ACT), a decision was made not to pathologize the sleeplessness, but relabel it as wakefulness, and refuse sleeping pills or methods to facilitate sleep. Instead, wakefulness was treated with active acceptance, and time was used productively or in light leisure activities such as watching motion pictures or reading. It is extremely important to note that the experience of the author was not of intense fatigue and weariness with a frustrated urge to sleep; rather the experience was of ongoing alertness and high functioning. In addition, the author was intensely fatigued and sleeping over 9 hours a night prior to dexamethasone.
The hypothesis This experience is completely at odds with the experience of subjects in sleep deprivation experiments, or subject to sleep deprivation in interrogation procedures. That weeks went by with barely any sleep but continued alert wakefulness and high functioning demands explanation, even as it contradicts current notions of the physiological and neurological necessity of sleep. The hypothesis proposed here then is that although sleep is a proximate physiological need under normal conditions, it is not an ultimate physiological need. That is, it is conceivable that a human organism could evolve under conditions where sleep was not beneficial, and therefore lack the mechanisms and need for sleep.
Analogies for understanding Consider, pain, nausea, and illness fatigue - all arise from signals to immobilise or protect the body. Immobilization to protect wounds, vomiting and nausea to void and avoid toxins, and rest and immobilisation during healing. The immobilisation itself is not a physiological need, but performs a protective function. The bodily signals to immobilization are peripheral nervous system or central nervous system events, or cytokine signalling in the case of illness. These signals are not considered pathological, but valid targets for symptom intervention. Pain and nausea are also treated, in the knowledge that so long as their protective function (wound protection, toxin avoidance) is maintained, then it is safe to do so. The signal is a proximate mechanism, that serves an ultimate evolutionary function. Here it is proposed that sleep is in the same class of phenomena. Sleep acts to immobilise the human ancestor during times of peak feline predation [1]. The signal to sleep is somnolence feelings, which are cumulative with prolonged wakefulness at night. This is consistent with increasing risk of predation with time mobile at night, due to scent and
sound tracking and predator stalking. It is also consistent with some degree of return of wakefulness in the daylight hours, as well as tendencies for sleep to cluster at peak predation times such as the crepuscule hours. If this is correct, then sleep is a mechanism for an ecological aim, a proximate signal causes discomfort if ignored, which is cumulative, but in of itself is not harmful. If correct, then how are experiments that seem to show the importance of sleep for memory consolidation [2]and other cognitive functions [3] to be reconciled? For this consider an even more radical corollary hypothesis; sleep does not provide neurological benefits, but comes at a cost. Sleep causes neurological deficits, a cost paid in trade-off to the ecological benefit of predator avoidance, and the processes observed in experiments are not benefits of sleep, but compensatory mechanisms to correct sleep induced deficits. It has been observed that during sleep the computational complexity and connectivity of the brain becomes severely restricted compared to the brain activity during consciousness. The idea that such restricted activity is necessary “rest” is assumption; it is just as likely that continuing high connectivity is enhancing, and periods of low connectivity costly. In support of this, the author increased in work productivity over weeks, with no noticeable impact on social interactions.
Mechanisms If this hypothesis is correct, then what signal is dexamethasone interrupting to cause the wakefulness? One possibility is effects on sympathetic amines and receptor systems [4]. However, recent research has decoupled arousal from wakefulness, such that increased arousal could not explain alone dexamethasone wakefulness [5]. A second possibility is
that sleep is signalled by cytokines, in a similar way to illness fatigue [6]. Dexamethasone is a powerful immune suppressive, which adds plausibility to this possibility. However, if this was correct, a diversity immune suppressive drugs would cause wakefulness, which is not the case. Lastly, dexamethasone influences amino acid neurotransmitter function, changing the ratio of glutamate to GABA signalling in various brain regions [7]. GABA modulators are well known sleep inducers, so this hypothesis has some plausibility.
Conclusion The evidence and arguments presented here suggest that sleep is not a necessity, and that the need for sleep can be pharmacological reduced without clear evidence of harm over extended periods. Dexamethasone itself is a toxic drug, causing a multitude of metabolic and Cushingoid adverse effects, cumulative with time and dose. But it is conceivable that the specific mechanism of dexamethasone wakefulness might be isolated; and such would be not a sleeping pill, but a true wakefulness pill.
References
1.
Anderson JR. Sleep, sleeping sites, and sleep‐related activities: awakening to their
significance. American Journal of Primatology. 1998;46(1):63-75.
2.
Siegel
JM.
The
REM
sleep-memory
consolidation
hypothesis.
Science.
2001;294(5544):1058-63. 3.
Walker MP, Stickgold R. Sleep, memory, and plasticity. Annu Rev Psychol.
2006;57:139-66. 4.
Wurtman RJ, Axelrod J. Control of enzymatic synthesis of adrenaline in the adrenal
medulla by adrenal cortical steroids. Journal of Biological Chemistry. 1966;241(10):2301-5. 5.
de Lecea L, Carter ME, Adamantidis A. Shining light on wakefulness and arousal.
Biological psychiatry. 2012;71(12):1046-52. 6.
Meyers CA, Albitar M, Estey E. Cognitive impairment, fatigue, and cytokine levels in
patients
with
acute
myelogenous
leukemia
or
myelodysplastic
syndrome.
Cancer.
2005;104(4):788-93. 7.
Di S, Maxson MM, Franco A, Tasker JG. Glucocorticoids regulate glutamate and GABA
synapse-specific retrograde transmission via divergent nongenomic signaling pathways. Journal of Neuroscience. 2009;29(2):393-401.
The author has no conflicts of interest to declare.
S0306-9877(19)31039-4 https://doi.org/10.1016/j.mehy.2019.109433 YMEHY 109434
To appear in:
Medical Hypotheses
Received Date: Revised Date: Accepted Date:
14 September 2019 7 October 2019 10 October 2019
Please cite this article as: J.C. Ashton, A radical hypothesis on the nature of sleep, Medical Hypotheses (2019), doi: https://doi.org/10.1016/j.mehy.2019.109433
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Ltd.
For: Medical Hypotheses 31 July 2019
A radical hypothesis on the nature of sleep.
John C. Ashton Department of Pharmacology & Toxicology, Otago School of Biomedical Sciences, University of Otago, Dunedin, New Zealand. +6434793040 [email protected]
Running Head: False research findings.
Keywords: dexamethasone; proximate and ultimate mechanisms; sleep; wakefulness
Abstract Dexamethasone has been observed to cause night-time wakefulness without accompanying fatigue. It is proposed here that the drug interrupts a sleep signal, and that altough sleep has an ultimate ecological function, this signal is a proximate mechanism but not an ultimate physiological necessity, such that sleep is not a necessity.
Introduction The background to the proposed hypothesis is a medical event experienced by the author in early 2019. Discharged from hospital with secondary brain metastases, the author was prescribed alectinib for ALK-positive cancer, and dexamethasone to control brain oedema during the initial phases of alectinib treatment. The dose of dexamethasone started at 16 mg/day, tapered to 14mg/day at day 3, 12 mg/day at day 7, and then tapering by 2 mg/day increments week to hold at 4 mg/day, continued until MRI scan confirmed a strong tumour response to alectinib, at which point dexamethasone was tapered further to zero. In the time when the author was taking 4 mg/day dexamethasone, he barely slept. In the first week, complete wakefulness through the night was usual, and in subsequent weeks more than one hour of sleep a night unusual, but with progressively more sleep with dose reductions; though only to approximately 3 hours a night at 4 mg/day. Surprisingly, the author was not fatigued, and did not have the urge to sleep during the day. Importantly, although being told that dexamethasone causes insomnia, as he was practicing Acceptance and Commitment Therapy (ACT), a decision was made not to pathologize the sleeplessness, but relabel it as wakefulness, and refuse sleeping pills or methods to facilitate sleep. Instead, wakefulness was treated with active acceptance, and time was used productively or in light leisure activities such as watching motion pictures or reading. It is extremely important to note that the experience of the author was not of intense fatigue and weariness with a frustrated urge to sleep; rather the experience was of ongoing alertness and high functioning. In addition, the author was intensely fatigued and sleeping over 9 hours a night prior to dexamethasone.
The hypothesis This experience is completely at odds with the experience of subjects in sleep deprivation experiments, or subject to sleep deprivation in interrogation procedures. That weeks went by with barely any sleep but continued alert wakefulness and high functioning demands explanation, even as it contradicts current notions of the physiological and neurological necessity of sleep. The hypothesis proposed here then is that although sleep is a proximate physiological need under normal conditions, it is not an ultimate physiological need. That is, it is conceivable that a human organism could evolve under conditions where sleep was not beneficial, and therefore lack the mechanisms and need for sleep.
Analogies for understanding Consider, pain, nausea, and illness fatigue - all arise from signals to immobilise or protect the body. Immobilization to protect wounds, vomiting and nausea to void and avoid toxins, and rest and immobilisation during healing. The immobilisation itself is not a physiological need, but performs a protective function. The bodily signals to immobilization are peripheral nervous system or central nervous system events, or cytokine signalling in the case of illness. These signals are not considered pathological, but valid targets for symptom intervention. Pain and nausea are also treated, in the knowledge that so long as their protective function (wound protection, toxin avoidance) is maintained, then it is safe to do so. The signal is a proximate mechanism, that serves an ultimate evolutionary function. Here it is proposed that sleep is in the same class of phenomena. Sleep acts to immobilise the human ancestor during times of peak feline predation [1]. The signal to sleep is somnolence feelings, which are cumulative with prolonged wakefulness at night. This is consistent with increasing risk of predation with time mobile at night, due to scent and
sound tracking and predator stalking. It is also consistent with some degree of return of wakefulness in the daylight hours, as well as tendencies for sleep to cluster at peak predation times such as the crepuscule hours. If this is correct, then sleep is a mechanism for an ecological aim, a proximate signal causes discomfort if ignored, which is cumulative, but in of itself is not harmful. If correct, then how are experiments that seem to show the importance of sleep for memory consolidation [2]and other cognitive functions [3] to be reconciled? For this consider an even more radical corollary hypothesis; sleep does not provide neurological benefits, but comes at a cost. Sleep causes neurological deficits, a cost paid in trade-off to the ecological benefit of predator avoidance, and the processes observed in experiments are not benefits of sleep, but compensatory mechanisms to correct sleep induced deficits. It has been observed that during sleep the computational complexity and connectivity of the brain becomes severely restricted compared to the brain activity during consciousness. The idea that such restricted activity is necessary “rest” is assumption; it is just as likely that continuing high connectivity is enhancing, and periods of low connectivity costly. In support of this, the author increased in work productivity over weeks, with no noticeable impact on social interactions.
Mechanisms If this hypothesis is correct, then what signal is dexamethasone interrupting to cause the wakefulness? One possibility is effects on sympathetic amines and receptor systems [4]. However, recent research has decoupled arousal from wakefulness, such that increased arousal could not explain alone dexamethasone wakefulness [5]. A second possibility is
that sleep is signalled by cytokines, in a similar way to illness fatigue [6]. Dexamethasone is a powerful immune suppressive, which adds plausibility to this possibility. However, if this was correct, a diversity immune suppressive drugs would cause wakefulness, which is not the case. Lastly, dexamethasone influences amino acid neurotransmitter function, changing the ratio of glutamate to GABA signalling in various brain regions [7]. GABA modulators are well known sleep inducers, so this hypothesis has some plausibility.
Conclusion The evidence and arguments presented here suggest that sleep is not a necessity, and that the need for sleep can be pharmacological reduced without clear evidence of harm over extended periods. Dexamethasone itself is a toxic drug, causing a multitude of metabolic and Cushingoid adverse effects, cumulative with time and dose. But it is conceivable that the specific mechanism of dexamethasone wakefulness might be isolated; and such would be not a sleeping pill, but a true wakefulness pill.
References
1.
Anderson JR. Sleep, sleeping sites, and sleep‐related activities: awakening to their
significance. American Journal of Primatology. 1998;46(1):63-75.
2.
Siegel
JM.
The
REM
sleep-memory
consolidation
hypothesis.
Science.
2001;294(5544):1058-63. 3.
Walker MP, Stickgold R. Sleep, memory, and plasticity. Annu Rev Psychol.
2006;57:139-66. 4.
Wurtman RJ, Axelrod J. Control of enzymatic synthesis of adrenaline in the adrenal
medulla by adrenal cortical steroids. Journal of Biological Chemistry. 1966;241(10):2301-5. 5.
de Lecea L, Carter ME, Adamantidis A. Shining light on wakefulness and arousal.
Biological psychiatry. 2012;71(12):1046-52. 6.
Meyers CA, Albitar M, Estey E. Cognitive impairment, fatigue, and cytokine levels in
patients
with
acute
myelogenous
leukemia
or
myelodysplastic
syndrome.
Cancer.
2005;104(4):788-93. 7.
Di S, Maxson MM, Franco A, Tasker JG. Glucocorticoids regulate glutamate and GABA
synapse-specific retrograde transmission via divergent nongenomic signaling pathways. Journal of Neuroscience. 2009;29(2):393-401.
The author has no conflicts of interest to declare.