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What is the normal temperature for the human brain? LMB in Cambridge discovers we are more hot-headed than we thought



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Humans are more hot-headed than we thought, scientists at the MRC Laboratory of Molecular Biology in Cambridge have discovered.

They have shown that the temperature in our brain varies much more widely than previously assumed by age, sex, menstrual cycle, brain region and, most notably, by time of day.

And they were stunned to discover that parts of the healthy human brain routinely exceeded 40°C - well above the normal body core temperature of 36.1 to 37.2°C. Such temperatures were most often recorded during the afternoon in core brain regions of females in the post-ovulation phase of their menstrual cycle.

Brain temperature in the morning versus the evening in post-ovulation (luteal) females and males. Picture: N Rzechorzek/MRC LMB/Brain
Brain temperature in the morning versus the evening in post-ovulation (luteal) females and males. Picture: N Rzechorzek/MRC LMB/Brain

The findings could have a raft of implications, including for the treatment of brain-injured patients, the diagnosis and management of several brain disorders and our understanding of how the brain works.

“For decades, we've known that brain cells are very sensitive to changes in temperature,” says Nina Rzechorzek, from John O’Neill’s group in the LMB’s Cell Biology division, who led the research. “Because of this, clinicians have assumed that healthy brain temperature must not vary and should be the same as the body core. Problem is, unlike many other things we monitor in patients there is no reference range for healthy human brain temperature to compare patient data with.

“As a result, some patients with brain injury undergo interventions to achieve a normal brain temperature without knowing what is truly normal for the human brain.”

Historical data from non-human primates has suggested that brain temperature varies according to time and space, and is higher than core body temperature.

Brain temperature in the morning in post-ovulation females. Picture: N Rzechorzek/MRC LMB/Brain
Brain temperature in the morning in post-ovulation females. Picture: N Rzechorzek/MRC LMB/Brain

“To help clinicians understand and interpret brain temperature data from patients, we set out to answer a very simple question: what is the normal temperature of the human brain?

“Here we faced a Catch-22 challenge. Brain temperature can be measured directly in patients with moderate to severe brain injury using brain probes, but the values obtained might be abnormal because of their brain injury.

Brain temperature in the morning in males. Picture: N Rzechorzek/MRC LMB/Brain
Brain temperature in the morning in males. Picture: N Rzechorzek/MRC LMB/Brain

“We cannot use brain probes in healthy humans but we can obtain very accurate and precise estimates of brain temperature using a special brain scanning technique called magnetic resonance spectroscopy, or MRS,” explains Nina.

The LMB collaborated with neurocritical care specialists at NHS Lothian, Edinburgh, and Addenbrooke’s Hospital in Cambridge for the study, which drew on the Europe-wide CENTER-TBI database of patients with traumatic brain injury to find patients who had their brain temperature measured continuously and directly in intensive care.

The temperatures ranged from 32.6 to 42.3°C and mean brain temperature exceeded body temperature, but only one quarter of them displayed a daily rhythm in brain temperature.

Brain temperature in the afternoon in post-ovulation females. Picture: N Rzechorzek/MRC LMB/Brain
Brain temperature in the afternoon in post-ovulation females. Picture: N Rzechorzek/MRC LMB/Brain

The group compared these findings with data from healthy brains by recruiting 20 male and 20 female volunteers, aged 20-40 and from 15 countries, for non-invasive brain thermometry in Edinburgh.

MRS was used to measure temperature in 82 brain locations in the morning, afternoon, and late evening.

The work included the first thermal imaging of the hypothalamus - the brain region responsible for regulating temperature and the body clock.

Brain temperature in the afternoon in males. Picture: N Rzechorzek/MRC LMB/Brain
Brain temperature in the afternoon in males. Picture: N Rzechorzek/MRC LMB/Brain

Aided by the LMB Visual Aids department, they incorporated their results into HEATWAVE, a freely-available 4D map of healthy human brain temperature.

“We found that healthy brain temperature ranged from 36.1 to 40.9 degrees Celsius and mean brain temperature exceeded body temperature,” explains Nina.

“Brain temperature was 0.4 to 0.8 degrees higher in females in the post-ovulation phase of their menstrual cycle relative to other females and males.

. Brain temperature in the late evening in post-ovulation females. Picture: N Rzechorzek/MRC LMB/Brain
. Brain temperature in the late evening in post-ovulation females. Picture: N Rzechorzek/MRC LMB/Brain

“Surprisingly healthy brain temperature increased with age especially in core brain regions and at any given moment temperature varied across the brain by 2.4 degrees.

“The highest temperatures were observed in the thalamus, a region located right in the centre of the brain.

“Importantly, brain temperature varied by time of day especially in core regions and was lowest at night just before bedtime.”

Brain temperature in the late evening in males. Picture: N Rzechorzek/MRC LMB/Brain
Brain temperature in the late evening in males. Picture: N Rzechorzek/MRC LMB/Brain

Using this information, they tested the clinical relevance of brain temperature monitoring in brain injured patients and found that the rhythm of brain temperature was one of the strongest single predictors of survival after traumatic brain injury.

“Whilst maximum and minimum brain temperatures did not predict survival, we found that patients lacking a daily rhythm in brain temperature had a 21-fold greater chance of dying in intensive care.

“Consistent with many other studies we found that ageing by 10 years increased the odds of death 11-fold, but in contrast to some other studies a warmer average brain temperature was associated with survival,” says Nina.

“We propose that daily brain temperature variation, not absolute brain temperature, better distinguishes normal brain function from its dysfunction.

“Further studies are needed to determine whether a daily rhythm in brain temperature is critical to brain health but our findings certainly raise questions about whether temperature-based interventions are appropriate for patients with traumatic brain injury and if so when and how they should be applied.”

The research raises the question of whether abnormal daily rhythm in brain temperature could be used as an early biomarker of neurodegeneration.

“Fundamentally, these results transform how we should think about human brain temperature, how it is normally controlled, how its variation might be interpreted in patients with brain injury and how its variation might change with healthy ageing and in age-related disease,” adds Nina.

“Moreover, knowing how much human brain temperature varies normally allows us to better model acute and chronic brain disorders in the lab, using human brain cells grown in a dish.”

Snapshot of the regions in which brain temperature was measured in healthy adults. Picture: N Rzechorzek/MRC LMB/Brain
Snapshot of the regions in which brain temperature was measured in healthy adults. Picture: N Rzechorzek/MRC LMB/Brain

The time-of-day variation could explain diurnal changes in cognitive performance and help us understand how brain temperature interacts with sleep.

Disruption to sleep caused, for example, by shift work or jet lag, is already known to have a negative impact on cognitive performance and mental health.

Healthy human brain temperature extremes showing relatively hot temperatures in post-ovulation females in the morning compared with coldest temperatures in males at night. Lighter yellow represents hotter temperatures. Picture: N Rzechorzek/MRC LMB/Brain
Healthy human brain temperature extremes showing relatively hot temperatures in post-ovulation females in the morning compared with coldest temperatures in males at night. Lighter yellow represents hotter temperatures. Picture: N Rzechorzek/MRC LMB/Brain

HEATWAVE is already being used to test how daily variation in human brain temperature interacts with molecular ‘clocks’ within human brain cells. This could help us understand temperature as a circadian timing cue and probe the true thermodynamics of brain function.

Meanwhile, the age-related temperature increase implies the brain’s capacity for cooling may deteriorate with age. This suggests other avenues for research. Could progressive failure to cool the brain influence the development of age-related brain disorders such as dementia?

Brain regions selected for temperature measurement using magnetic resonance spectroscopy shown as overlays on standard MRI brain scans in various planes. 80 regions were chosen in the cerebrum (shown from above, top left, and from the side, top right) and grouped into 4 concentric layers (top left). One region was chosen in the hypothalamus (Hypo; shown from top, side, and front view, bottom left to middle), and one region from the thalamus (Thal; shown from front view, bottom right). The hypothalamus is a key region for regulating many things including temperature, sleep, and body clocks. Picture: N Rzechorzek/Edinburgh Imaging/Brain
Brain regions selected for temperature measurement using magnetic resonance spectroscopy shown as overlays on standard MRI brain scans in various planes. 80 regions were chosen in the cerebrum (shown from above, top left, and from the side, top right) and grouped into 4 concentric layers (top left). One region was chosen in the hypothalamus (Hypo; shown from top, side, and front view, bottom left to middle), and one region from the thalamus (Thal; shown from front view, bottom right). The hypothalamus is a key region for regulating many things including temperature, sleep, and body clocks. Picture: N Rzechorzek/Edinburgh Imaging/Brain

“The brain is our most precious machine. Understanding the conditions under which it performs best will enable us to keep the brain healthier for longer and further our understanding of how the brain works,” Nina concludes.

The work was funded by UKRI MRC, Hannelore Kohl Stiftung, OneMind, Integra LifeSciences Corporation and NHS Lothian Research and Development Office.



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