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what happens to the brain when temperature increases
A sweating brain when the temperature of the brain is increased.

Brain Hyperthermia

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Brain hyperthermia also known as cerebral hyperthermia, is a normal physiological phenomenon that involves heat production when the brain is metabolically active. The brain temperature is usually a stable and tightly regulated homeostatic parameter. Under resting condition, there is a balance between heat production and dissipation in the brain,but this balance may shift in several physiological and pathological conditions leading to an impairment in heat dissipation, thus causing a pathological brain hyperthermia that can have a direct destruction to the brain cells. The brain accounts for about 20% of the total oxygen consumption and has a greater metabolic rate than the rest of the body.[1]

Increased temperature both from infective and non-infective cause can lead to irreversible damage and thus may lead to death. A temperature above 37 degree centigrade can be dangerous and its effect more significant from 38.5 degree centigrade and above.[2] There are lots of evidence that have shown the involvement of the central nervous system during hyperthermia and how vulnerable it becomes when its exposure to hyperthermia is prolonged or excessive. There are two non-infective causes of hyperthermia namely; Heat illness and Drug induced hyperthermia.[3]

Non-infective causes of Brain Hyperthermia

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An endurance athlete

Heat illness

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It is of two forms, namely;

  • Classical heatstroke: This occurs after exposure to extreme environmental conditions e.g heat waves.[3] Being able to cool the temperature to below 38.9 degree centigrade during a classical heatstroke within 60 mins, has shown a trend towards improved survival.[4]
  • Exertional heatstroke: This occurs after engaging in strenuous activities. It can be seen in endurance athletes and the military.[3]

Recovery from hyperthermia is most likely to occur if the person is not exposed to higher temperatures for a long period of time, as the risk of complications occurring is seen after prolonged exposure. Heatstroke has been seen to be associated with a mortality rate of 40% to 64%.[5]Heat stroke is said to occur when the brain temperature reaches temperature above 40.5 degree centigrade to 41 degree centigrade. At this temperature, the ability of the hypothalamus to regulate brain temperature becomes compromised and there could be increased intracerebral pressure.[6] A person who survives the complications may experience some persistent deficits in memory and attention, personality changes and brain lesions , thus resulting in global dementia.[7]



Drug induced hyperthermia

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Amphetamine drug

All addictive drugs induce behavioral, autonomic and psycho-emotional simulations which may reflect metabolic neural activation.[1] Opiates at low doses has been shown to increase whole body oxygen consumption and heat production, which points to metabolic activation but decreases these parameters at higher doses.[8][9] Cocaine when used in drug-naive animals was seen to increase their cerebral oxygen consumption and body temperature.[10] Amphetamine like substances e.g METH has shown to increase cerebral metabolism which effect is dose dependent.


METH are addictive drugs which can can cause hyperthermia and lead to brain damage with chronic use. They induce abnormal release of endogenous neurotransmitters, including glutamate and cathecholamines, some toxic products of their metabolism[ Nitric oxide, Arachidonic acid, Peroxynitrite] which are primary contributors to neural cell damage via oxidative stress.[1]


Cognitive Dysfunction as a result of Brain Hyperthermia

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Cognition involves mental processes such as memory, knowledge, attention, reasoning, problem solving as well as comprehension. Cognitive impairment can occur even if hyperthermia is mild and exposure is only for a short period of time. Cognitive changes due to hyperthermia can be observed after 1-2hrs of elevated temperature. Studies have shown the acute effect of hyperthermia on memory, attention and processing of information. Some of these cognitive processes are more affected by hyperthermia than the others.[3] In a study, it showed memory impairment in a number of healthy volunteers induced with hyperthermia at a temperature of 38.8 degree centigrade compared to when they were in normal temperature.[11]

Functional Neuroimaging has shown that the cognitive pathway is large and has various connections, many of which are affected acutely in brain hyperthermia. In a study , increase in activity was seen in the dorso-lateral prefrontal cortex which executes functions like memory, cognition and reasoning, also increased activity was seen in the intraparietal sulcus involved in processing and memory during acute cerebral hyperthermia.[12] Hyperthermia induced cognitive dysfunction, may also be due to alteration in cell signalling. In a study, Calcium/ Calmodulin- dependent protein kinase II [Ca MK II] involved involved in many signalling cascades and an important mediator for learning and memory has been seen to be affected by hyperthermia induced phosphorylation in neonatal rats leading to significant deficit in spatial memory and learning.[13]

Electroencephalography has been shown to detect short-term memory changes caused by brain hyperthermia. Although cases have shown recovery from acute cognitive dysfunction due to hyperthermia, some people are left with permanent changes in their attention, memory or personality and in some cases may lead to severe global dementia.[14]


Neurological effects due to Hyperthermia

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The effect of brain hyperthermia on neurological function can be seen in three stages:[3]

  1. Acute stage
  2. The Covalescent period
  3. The period of permanent deficit

Neurological effect of hyperthermia depends on the magnitude and duration of the increase in temperature. The acute stage of the neurological effects is seen to occur after a number of causes including heat illness and drugs. Acute neurological damage after drug induced hyperthermia has been reported to result from malignant hyperthermia and neuroleptic malignant syndrome.[15][16] The cerebellum has been shown to be the most predominantly affected brain region in cases of persistent neurological dysfunction. There have also been a report of Basal ganglia dysfunction after a heatstroke, and well seen after neuroleptic malignant syndrome. Hyperthermia has also been shown to hasten delayed cell death that follows an ischemic insult


Many findings on the neurological effects of hyperthermia have been seen on MRI after heatstroke. These radiological findings include: hemorrhage, oedematous changes, ischemia, encephalitis, atrophic changes. Diffusion weighted imaging [DWI] sensitive for detecting ischemic changes and Susceptibility weighted imaging sensitive for hemorrhage are useful in detecting heatstroke induced changes.[14]

Neurological effects due to hyperthermia in a developing brain

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In a study, it was found out that just 12 mins of exposure to 43 degree centigrade during embryonic development, could produce neuronal apoptosis and a reduction in the thickness of cortical grey matter.[17] The embryonic brain can be damaged by temperatures from 40 degree and above. It was shown that neural tube defect occurred in human embryo when exposed to hyperthermia during the equivalent period of neural groove closure (E23-E-25).[18] In embryo, exencephaly has been considered a specific neural tube defect induced by fever during early pregnancy.[19]

Mechanism of cerebral damage due to Hyperthermia

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Hyperthermia effect on the brain can be grouped into three broad areas, namely;[3]

  1. Cellular effects - Hyperthermia has been seen to cause deleterious effects on neuronal structure and function, disruption of electrochemical depolarization, trans-membrane ionic transport and disruption of cellular signalling mechanisms. The mitochondria and plasma membranes are the most sensitive cellular components of a neuron. The degree of cellular damage depends on the intensity of the heat stress and its duration.An irreversible alteration to protein structure occurs at temperature above 40 degree celscius and increases exponentially as the exposure time increases. Excitotoxicity occurs when neurons are damaged due to excessive exposure to excitatory neurotransmitters [ can be seen in METH]. The damage is as a result of the neurons being rendered susceptible to calcium influx which is capable of reducing ATP production, alter electrochemical gradients and stimulate caspase-dependent apoptosis.[3] Very high temperatures cause cell swelling and necrosis that becomes pronounced during or shortly after it. Hyperthermia has also been shown to produce apoptotic death in cortical neurons, cerebellar granule neurons, dorsal root ganglion neurons and septal neurons
  2. Local effects of hyperthermia- The expression of large numbers of proteins and anti-inflammatory cytokines are greatly affected during acute and recovery phases following a hyperthermic insult. The local effects of hyperthermia can be expressed as ischemia, hemorrhage, infarction, inflammatory changes, oedema which can be seen in a radiographical examination following an hyperthermic insult.[3]
  3. Systemic effect of hyperthermia- The Blood Brain Barrier [BBB] shows increased permeability at temperatures above 38-39 degree Celsius and thus allow increased transport of substances.[20] This increased permeability is thought to be the predominant factor in development of cerebral oedema in hyperthermic states.[3] Modest increase in core temperature, increases cerebral metabolic rates in some areas and decreases it in others. In extreme hyperthermic condition, mitochondria oxygen metabolism is seen to reduce in temperature above 40 degree Celsius.[21] This is likely to imply that mitochondria oxygen intake is impaired at higher temperature, but in the absence of raised lactate may indicate reduced cerebral metabolic activity and thus account for cognitive and neurological signs and symptoms.[3]

Heat shock proteins [HSP]

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They are a family of proteins produced by cells in response to stressful conditions like hyperthermia. They are seen predominantly in glia and purkinje cells. The CNS has shown consecutive expression of HSP 27 with noxious stimuli. HSP 70 found in purkinje cells usually have delayed production which may last for up to several hours thus rendering the cells at risk in it's immediate phase to hyperthermia. These purkinje cells are in large amount in the cerebellum, thus rendering cerebellar damage to occur more frequently. It has also been noted that purkinje cells have heme oxygenase [HO]^-1 which aggrevates heat shock injury.[3]

The response of heat shock proteins to hyperthermia is dependent on their location. The intracellularly located ones play a protective role in correcting misfolded proteins, prevent protein aggregation, transport proteins and support processing antigen and it's presentation, also helps limits apoptosis. HSP located extracellularly, may be immuno-stimulatory and appear to induce cytokine release or provide recognition sites for natural killers.[22][23]


Caspase dependent cell death

Caspase

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They are cysteine proteases that regulates apoptosis and other cellular regulatory processes. Up stream caspase initiators (1, 2, 8, 9, 12) are involved in activating apoptotic pathways. Caspase activation follows heat stress in neuroblastoma cells. Caspase inhibitors appear to prolong neuronal survival after exposure to hyperthermia.

Recent works have shown the alteration of the kinase family involved in regulation of cellular metabolic pathways. C-jun NH2-terminal protein kinase [JNK] 2 and 3 are involved in regulation of cell differentiation and development, including induction of apoptosis in response to neuronal stress. Heat stress alters its function in its phosphorylation state.[3]





Methodologies used in assessing Brain Hyperthermia

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  • Correlation between temperature and biological significance
  • Tight association of temperature change with sleep wakefulness cycle
  • Localized temperature changes to visual and auditory stimuli in specific thalamic structures involved in processing stimuli
  • Correlation between temperature and EEG[Electroencephalography] changes


Methods adopted for reducing Brain Hyperthermia

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  1. The use of acetaminophen to control elevated temperature during stroke. This method however, does not produce a robust effect to have much clinical impact.[24]
  2. Cooling below 37 degree centigrade has shown a level of protection in animal ischemia models.[25]

See Also

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References

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  1. ^ a b c Eugene, A. Kiyatkin (2003-12-31). "Brain Hyperthermia During Physiological and Pathological Conditions: Causes, Mechanisms, and Functional Implications". Current Neurovascular Research. 1 (1): 77–90. doi:10.2174/1567202043480233.
  2. ^ Lee, Byung Ho; Inui, Daisuke; Suh, Gee Young; Kim, Jae Yeol; Kwon, Jae Young; Park, Jisook; Tada, Keiichi; Tanaka, Keiji; Ietsugu, Kenichi; Uehara, Kenji; Dote, Kentaro (2012-02-28). "Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study". Critical Care. 16 (1): R33. doi:10.1186/cc11211. ISSN 1364-8535. PMC 3396278. PMID 22373120.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  3. ^ a b c d e f g h i j k l Walter, Edward James; Carraretto, Mike (2016-07-14). "The neurological and cognitive consequences of hyperthermia". Critical Care. 20 (1): 199. doi:10.1186/s13054-016-1376-4. ISSN 1364-8535. PMC 4944502. PMID 27411704.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  4. ^ Vicario, Salvator J.; Okabajue, Reginald; Haltom, Thomas (1986-09-01). "Rapid cooling in classic heatstroke: Effect on mortality rates". The American Journal of Emergency Medicine. 4 (5): 394–398. doi:10.1016/0735-6757(86)90185-3. ISSN 0735-6757.
  5. ^ Pease, Sebastian; Bouadma, Lila; Kermarrec, Nathalie; Schortgen, Frédérique; Régnier, Bernard; Wolff, Michel (2009-08-01). "Early organ dysfunction course, cooling time and outcome in classic heatstroke". Intensive Care Medicine. 35 (8): 1454–1458. doi:10.1007/s00134-009-1500-x. ISSN 1432-1238.
  6. ^ Simon, Harvey B. (1993-08-12). "Hyperthermia". New England Journal of Medicine. 329 (7): 483–487. doi:10.1056/NEJM199308123290708. ISSN 0028-4793. PMID 8332154.
  7. ^ Romero, Josué J.; Clement, Pamelia F.; Beiden, Clifford (2000-06-01). "Neuropsychological Sequelae of Heat Stroke: Report of Three Cases and Discussion". Military Medicine. 165 (6): 500–503. doi:10.1093/milmed/165.6.500. ISSN 0026-4075.
  8. ^ LYNCH, THOMAS J.; ADLER, MARTIN W.; EISENSTEIN, TOBY K. (1990-06). "Comparison of the Mechanisms of Interleukin-1 and Morphine-induced Hyperthermia in the Rat". Annals of the New York Academy of Sciences. 594 (1 Neuropeptides): 469–471. doi:10.1111/j.1749-6632.1990.tb40531.x. ISSN 0077-8923. {{cite journal}}: Check date values in: |date= (help)
  9. ^ Endoh, Hiroshi; Taga, Kiichiro; Yamakura, Tomohiro; Sato, Kazunori; Watanabe, Ippei; Fukuda, Satoru; Shimoji, Koki (1999-09). "Effects of naloxone and morphine on acute hypoxic survival in mice". Critical Care Medicine. 27 (9): 1929–1933. doi:10.1097/00003246-199909000-00035. ISSN 0090-3493. {{cite journal}}: Check date values in: |date= (help)
  10. ^ Robinson, Roderick; Iida, Hiroki; O'Brien, Thomas P.; Pane, Maria A.; Traystman, Richard J.; Gleason, Christine A. (2000-07-01). "Comparison of cerebrovascular effects of intravenous cocaine injection in fetal, newborn, and adult sheep". American Journal of Physiology-Heart and Circulatory Physiology. 279 (1): H1–H6. doi:10.1152/ajpheart.2000.279.1.h1. ISSN 0363-6135.
  11. ^ Communications, Florida International University-Digital. "School of Education and Human Development". case.fiu.edu. Retrieved 2021-11-14.
  12. ^ Jiang, Qingjun; Yang, Xiao; Liu, Kai; Li, Bo; Li, Li; Li, Min; Qian, Shaowen; Zhao, Lun; Zhou, Zhenyu; Sun, Gang (2013-04-16). "Hyperthermia impaired human visual short-term memory: An fMRI study". International Journal of Hyperthermia. 29 (3): 219–224. doi:10.3109/02656736.2013.786141. ISSN 0265-6736.
  13. ^ Xiong, Yufang; Zhou, Hui; Zhang, Lian (2014-04). "Influences of hyperthermia-induced seizures on learning, memory and phosphorylative state of CaMKIIα in rat hippocampus". Brain Research. 1557: 190–200. doi:10.1016/j.brainres.2014.02.026. ISSN 0006-8993. {{cite journal}}: Check date values in: |date= (help)
  14. ^ a b "HEATSTROKE: ITS CLINICAL PICTURE AND MECHANISM IN 36 CASES". QJM: An International Journal of Medicine. 1967-10. doi:10.1093/oxfordjournals.qjmed.a067127. ISSN 1460-2393. {{cite journal}}: Check date values in: |date= (help)
  15. ^ Labuda, Anna; Cullen, Nora (2006-01). "Brain injury following neuroleptic malignant syndrome: Case report and review of the literature". Brain Injury. 20 (7): 775–778. doi:10.1080/02699050600663022. ISSN 0269-9052. {{cite journal}}: Check date values in: |date= (help)
  16. ^ Forrest, Katharine M.L.; Foulds, Nicola; Millar, John S.; Sutherland, Paul D.; Pappachan, V. John; Holden, Samantha; Mein, Rachael; Hopkins, Philip M.; Jungbluth, Heinz (2015-02). "RYR1-related malignant hyperthermia with marked cerebellar involvement – A paradigm of heat-induced CNS injury?". Neuromuscular Disorders. 25 (2): 138–140. doi:10.1016/j.nmd.2014.10.008. ISSN 0960-8966. {{cite journal}}: Check date values in: |date= (help)
  17. ^ Hinoue, Atsushi; Fushiki, Shinji; Nishimura, Yoshihiko; Shiota, Kohei (2001-12). "In utero exposure to brief hyperthermia interferes with the production and migration of neocortical neurons and induces apoptotic neuronal death in the fetal mouse brain". Developmental Brain Research. 132 (1): 59–67. doi:10.1016/S0165-3806(01)00295-4. {{cite journal}}: Check date values in: |date= (help)
  18. ^ Smith, M. S. R.; Upfold, J. B.; Edwards, M. J.; Shiota, K.; Cawdell-Smith, J. (1992). "The induction of neural tube defects by maternal hyperthermia: a comparison of the guinea-pig and human". Neuropathology and Applied Neurobiology. 18 (1): 71–80. doi:10.1111/j.1365-2990.1992.tb00765.x. ISSN 1365-2990.
  19. ^ Shiota, Kohei; Opitz, John M. (1982). "Neural tube defects and maternal hyperthermia in early pregnancy: Epidemiology in a human embryo population". American Journal of Medical Genetics. 12 (3): 281–288. doi:10.1002/ajmg.1320120306. ISSN 1096-8628.
  20. ^ Kiyatkin, E.A.; Sharma, H.S. (2009-07). "Permeability of the blood–brain barrier depends on brain temperature". Neuroscience. 161 (3): 926–939. doi:10.1016/j.neuroscience.2009.04.004. ISSN 0306-4522. {{cite journal}}: Check date values in: |date= (help)
  21. ^ Cremer, Olaf L.; Kalkman, Cor J. (2007), "Cerebral pathophysiology and clinical neurology of hyperthermia in humans", Progress in Brain Research, Elsevier, pp. 153–169, retrieved 2021-11-14
  22. ^ Multhoff, Gabriele (2007-11). "Heat shock protein 70 (Hsp70): Membrane location, export and immunological relevance". Methods. 43 (3): 229–237. doi:10.1016/j.ymeth.2007.06.006. ISSN 1046-2023. {{cite journal}}: Check date values in: |date= (help)
  23. ^ Didelot, C.; Schmitt, E.; Brunet, M.; Maingret, L.; Parcellier, A.; Garrido, C., "Heat Shock Proteins: Endogenous Modulators of Apoptotic Cell Death", Molecular Chaperones in Health and Disease, Berlin/Heidelberg: Springer-Verlag, pp. 171–198, retrieved 2021-11-14
  24. ^ Dippel, Diederik WJ; van Breda, Eric J.; van der Worp, H. Bart; van Gemert, H. Maarten A.; Meijer, Ron J.; Kappelle, L. Jaap; Koudstaal, Peter J.; the PISA-investigators. (2003-02-06). "Effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute ischemic stroke PISA, a phase II double-blind, randomized, placebo-controlled trial [ISRCTN98608690]". BMC Cardiovascular Disorders. 3 (1): 2. doi:10.1186/1471-2261-3-2. ISSN 1471-2261.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  25. ^ Barone, Frank C; Feuerstein, Giora Z; White, Raymond F (1997-01-01). "Brain Cooling During Transient Focal Ischemia Provides Complete Neuroprotection". Neuroscience & Biobehavioral Reviews. 21 (1): 31–44. doi:10.1016/0149-7634(95)00080-1. ISSN 0149-7634.
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Methamphetamine induced neurotoxicity

Heatstroke induced cerebellar atrophy-clinical cause,CT & MRI findings

Neurogenic fever

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