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Title: 1 
Neurophysiology of brain temperature dysregulation in humans 2 
Authors: 3 
Christian Behler1,2,3, Michael Fay1,2,3, Saadallah Ramadan1,2,3, Michael 4 
Breakspear2,3,4, Anna Behler3,4,* 5 
Affiliations: 6 
1Mark Hughes Foundation Centre for Brain Cancer Research, University of 7 
Newcastle, NSW, Australia 8 
2School of Medicine and Public Health, College of Medicine, Health and Wellbeing, 9 
University of Newcastle, NSW, Australia 10 
3Hunter Medical Research Institute, New Lambton Heights, NSW, Australia 11 
4School of Psychological Sciences, College of Engineering, Science and the 12 
Environment, University of Newcastle, NSW, Australia 13 
 14 
Running head: Brain temperature dysregulation in humans 15 
*Correspondence: Anna Behler 16 
 School of Psychological Sciences 17 
University Drive 18 
Callaghan NSW 2308 19 
Australia 20 
e-mail: anna.behler@newcastle.edu.au 21 
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Abstract 28 
Brain temperature, a fundamental modulator of neural function, remains dramatically 29 
understudied despite its critical role in health and disease. This review synthesizes 30 
current understanding of brain thermoregulation and its disruption in neurological 31 
conditions, addressing a significant knowledge gap in neuroscience. We examined 32 
the physiological mechanisms maintaining brain temperature homeostasis, including 33 
the interplay between cerebral blood flow, metabolism, and cerebrospinal fluid 34 
dynamics. Analysis of publication trends reveals brain temperature research is 35 
underrepresented by 7- to 37-fold compared to other brain physiological parameters, 36 
despite comparable clinical relevance. We evaluated current non-invasive 37 
measurement techniques, particularly magnetic resonance-based thermometry, 38 
highlighting advances and limitations for clinical application. The review presents 39 
evidence for distinct temperature dysregulation patterns in neurological diseases. In 40 
Alzheimer's disease, we propose a theoretical framework of early-stage 41 
hyperthermia driven by neuroinflammation and hypermetabolism, transitioning to 42 
late-stage hypothermia with metabolic decline. Brain tumors exhibit contrasting 43 
thermal profiles: glioblastomas frequently present as hypothermic due to necrotic 44 
cores acting as metabolic voids, while melanoma metastases show hyperthermia 45 
from sustained metabolic activity. These temperature alterations may influence 46 
disease progression through effects on protein aggregation, cellular metabolism, and 47 
neuron-glial interactions. Looking forward, brain temperature monitoring could 48 
provide biomarkers for disease staging and treatment response. Additionally, 49 
understanding thermal limits becomes urgent as climate change exposes vulnerable 50 
populations with compromised thermoregulation to extreme heat. This review 51 
establishes brain temperature as an overlooked but essential axis in 52 
neurophysiology, calling for increased research attention to address fundamental 53 
questions about thermal regulation in health and disease. 54 
 55 
Keywords 56 
 57 
brain temperature, thermoregulation, Alzheimer's disease, glioblastoma, magnetic 58 
resonance thermometry 59 
 60 
1 Introduction 61 
 62 
Temperature is one of medicine's most fundamental vital signs, with deviations of 63 
even 1-2 °C often triggering immediate clinical intervention. Yet a striking paradox 64 
exists in neuroscience: while body temperature is meticulously monitored in virtually 65 
every clinical setting and extensively studied across medical disciplines, brain 66 
temperature remains largely overlooked despite the brain's unique metabolic 67 
intensity and thermal vulnerability. 68 
This oversight becomes evident when examining the neuroscience literature itself 69 
(Fig. 1). Among brain-specific physiological parameters, research on brain 70 
temperature is markedly underrepresented. Between 1990 and 2025, brain 71 
temperature publications are outnumbered 7-fold by brain oxygenation papers, 14-72 
fold by intracranial pressure studies, and even 37-fold by cerebral blood flow (CBF) 73 
research. This disparity indicates that brain temperature receives a fraction of the 74 
research attention given to other fundamental physiological parameters. 75 
Why does this matter? The brain's exceptional metabolic intensity makes it uniquely 76 
vulnerable to thermal disruption. Consuming ~20% of the body's oxygen despite 77 
comprising only ~2% of its mass, the brain generates roughly ten times more heat 78 
per gram than the average tissue (1). To minimize metabolic costs, the brain 79 
optimizes energy efficiency through sparse communication, efficient network 80 
organization, predictive coding, and optimized behavior planning (2). These 81 
computational strategies operate within strict thermal constraints. In the human 82 
cerebrum, the temperature coefficient (Q₁₀) is ~2.3 within physiological ranges (3), 83 
meaning the cerebral metabolic rate changes by ~9% for every 1°C deviation. Peak 84 
energy efficiency for neuronal signaling occurs near 37°C (4). The brain's 85 
computational strategies operate within these strict thermal constraints, as neural 86 
activity and temperature are bidirectionally coupled: neurons generate heat through 87 
metabolic activity, while temperature in turn modulates firing rates, synaptic 88 
transmission, and network dynamics. 89 
A recent comprehensive study revealed the remarkable complexity of human brain 90 
temperature regulation (5). Brain temperature can range from 36.1 to 40.9°C in 91 
healthy individuals, with differences of several degrees possible between brain and 92 
body temperature, and substantial variation across brain regions with deeper 93 
structures like the thalamus being warmest. 94 
Temperature is further influenced by sex, circadian rhythms, and age, though age 95 
effects remain unresolved, with recent studies reporting contradictory findings of both 96 
age-related increases (5) and decreases (6, 7) in brain temperature. If such basic 97 
physiological patterns remain unresolved, our understanding of temperature's role in 98 
disease states is even more limited. Yet beyond these empirical uncertainties lies a 99 
more fundamental question: how can neurons, which are highly temperature-100 
sensitive, function reliably across the broad thermal variation observed in healthy 101 
individuals? As detailed in Section 2, the resolution involves three factors: the 102 
distinction between population variability and individual stability, active compensatory 103 
mechanisms that maintain neural function across thermal fluctuations, and the 104 
importance of timescale, where slow changes permit adaptation while rapid 105 
transients may serve as physiological signals. Given the temperature sensitivity of 106 
protein aggregation, cellular metabolism, and inflammatory responses, temperature 107 
dysregulation could potentially contribute to disease processes in Alzheimer's 108 
disease and brain cancer. This possibility suggests that the assumption that body 109 
temperature adequately reflects brain temperature may need reconsideration. 110 
This review synthesizes current understanding of brain thermoregulation and its 111 
relevance to health and disease. We first outline the fundamental physiological 112 
principles and non-invasive measurement approaches. We then examine how 113 
neurodegenerative diseases and brain cancer may push thermoregulatory systems 114 
to their limits. The review concludes with an outlook on the broader implications of 115 
brain temperature regulation, including its relevance in the context of emerging 116 
health challenges, including the impact of a warming climate. 117 
 118 
2 Thermoregulation in the brain 119 
Brain thermoregulation encompasses the physiological processes that maintain brain 120 
tissue temperature within optimal ranges for neural function, achieving thermal 121 
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 1172 
Figures and Tables 1173 
 1174 
Figure Legends 1175 
 1176 
Figure 1. Publication counts for four brain-specific physiological parameters. The figure 1177 
shows the number of publications on cerebral blood flow, intracranial pressure, brain 1178 
oxygenation, and brain temperature (red) between 1990 and 2025. Brain temperature yields 1179 
7- to 37-fold fewer publications than the other parameters. The dashed red reference line 1180 
indicates the number of brain temperature publications for visual comparison; arrows denote 1181 
fold-differences. Publication counts and search methodology are detailed in the 1182 
Supplemental Material. 1183 
Figure 2. Thermoregulatory response to neuronal activity. (A) In the resting state, baseline 1184 
neuronal activity results in a relatively homogeneous temperature distribution, as indicated 1185 
by the background color. (B) Increased neuronal activity raises metabolic heat production, 1186 
leading to vasodilation and enhanced blood flow. The resulting temperature gradient, with 1187 
localized heat accumulation around active neurons and cooling near arteries, supports 1188 
thermal homeostasis over time. 1189 
Figure 3. Non-invasive Magnetic Resonance (MR)-based brain thermometry methods. (A) 1190 
With Proton Resonance Frequency (PRF) chemical shift thermometry, the absolute 1191 
temperature in a voxel is determined by tracking the water resonance frequency relative to 1192 
the temperature-independent N-acetylaspartate (NAA) peak from water-unsuppressed MR 1193 
spectroscopy. (B) By measuring the temperature-induced phase shift between two time 1194 
points, PRF phase shift thermometrydetects relative temperature changes. As an example, 1195 
simulated phase images before and during heat treatment (HT) with hypothetical cooling 1196 
(blue) and heating (red) regions are subtracted to generate a temperature difference (ΔT) 1197 
map. (C) Diffusion-weighted imaging (DWI) thermometry estimates temperature based on 1198 
the free diffusion coefficient of water molecules in the cerebrospinal fluid (CSF). 1199 
Figure 4. Hypothesized temperature dysregulation in Alzheimer's disease. (A) In the pre-1200 
symptomatic phase of AD, neuronal hyperexcitability may contribute to a hyperthermal 1201 
environment. Hypertrophic microglia, atrophic astrocytes, and early amyloid-β plaque 1202 
formation further characterize this stage. (B) As AD progresses into later stages, 1203 
accumulation of tau in neurofibrillary tangles (τ-tangles) and neuronal dysfunction leads to a 1204 
reduced metabolic rate, likely resulting in a hypothermal state. Dystrophic microglia, reactive 1205 
astrocytes, increased τ-tangles and amyloid-β plaque deposition also mark advanced AD 1206 
stages, along with dilated, stiff blood vessels reflecting neurovascular dysregulation. 1207 
Figure 5. Hypothesized temperature profiles in brain tumors. (A) Glioblastoma (GBM) 1208 
exhibits a complex thermal landscape characterized by a colder necrotic core, surrounded 1209 
by metabolically active tumor tissue generating heat. The necrotic center, lacking metabolic 1210 
activity, absorbs heat from surrounding regions, contributing to the overall hypothermic 1211 
presentation frequently observed in GBMs. The inset highlights critical interactions in the 1212 
tumor microenvironment: (1) activated astrocytes promoting tumor proliferation through 1213 
direct cell-cell contacts, (2) neurons releasing signaling factors facilitating tumor cell 1214 
invasion, and (3) irregular, leaky blood vessels typical of tumor angiogenesis that cannot 1215 
efficiently regulate heat exchange. (B) Brain metastases exhibit varying temperature profiles 1216 
depending on histology and vascular density. Melanoma metastases (shown) display higher 1217 
and more uniform temperatures due to widespread metabolically active cancer cells with 1218 
hyperactive mitochondria, combined with dense vascularization and absence of extensive 1219 
necrotic cores. In contrast, hypovascular metastases (e.g., lung adenocarcinoma) may 1220 
present as hypothermic. 1221 
 1222 
Tables 1223 
 1224 
CATEGORY REFERENCE METHOD REPORTED 
TEMPERATUR
E / STATUS 
VARIATION / 
GRADIENT (ΔT) 
CALIBRATION 
/ NOTES 
HEALTHY 
CONTROLS 
Rzechorzek et 
al. (2022) 
¹H-MRS 
(3 T) 
Population 
Range: 
 
36.1–40.9°C 
(mean 38.5) 
Diurnal Amplitude: 
0.86-1.21°C 
(Stable intra-
individual rhythm) 
 
Deep nuclei 
(thalamus) ≈1.6°C 
warmer than cortex 
Phantom-
validated; 
sex/age effects 
 Verius et al. 
(2019) 
¹H-MRS 
(3 T) 
37.8 ± 1.4°C 
(mean) 
No consistent 
hemispheric 
difference 
Extensive 
phantom 
calibration 
ALZHEIMER
'S DISEASE 
Asfuroğlu et 
al. (2022) 
DWI 
(Ventricul
ar CSF) 
AD: 38.0°C / 
Healthy: 38.5°C 
(median) 
Significant 
(p=0.009) decrease 
(−0.5°C) in AD 
patients 
Validation 
against healthy 
controls 
BRAIN 
TUMORS 
Babourina-
Brooks et al. 
(2014) 
¹H-MRS Hyperthermic 
(Low-Grade) 
ΔT ≈+0.7°C 
(warmer than 
healthy tissue) 
Pediatric cohort; 
Closed cranium 
retains heat; 
Literature 
calibration 
 Menezes et al. 
(2024); 
Gorbach et al. 
(2004) 
Intraopera
tive IR 
Hypothermic* 
(High-
Grade/GBM) 
∆T≈-0.5 to -2.2°C 
(cooler than healthy 
tissue) 
Adult cohort; 
Exposed cortex 
subject to 
evaporative 
cooling. Trend: 
High-Grade is 
relatively cooler 
than Low-
Grade. 
 Menezes et al. 
(2024) 
Intraopera
tive IR 
Hypothermic* 
(Lung 
Metastasis) 
∆T≈ -3.5°C (cooler 
than healthy tissue) 
High-Res; 100% 
specificity in this 
cohort 
 Gorbach et al. 
(2004) 
Intraopera
tive IR 
Hyperthermic* 
(Melanoma 
Metastasis) 
∆T > +0.5°C 
(warmer than 
healthy tissue) 
In-situ reference 
(Thermometer/P
robe) 
ANIMAL 
MODELS 
Kiyatkin et al. 
(2002) 
Direct 
Probe in 
four male 
Long-
Evans 
rats, 
weighing 
400–500g 
≈36.5–37.5°C 
(Awake/Resting) 
Rapid activity-
dependent spikes 
(+0.1–1.8°C) 
 
 
Latency: 9–13s 
(precedes blood) 
 
Direct invasive 
(Gold Standard) 
 
Demonstrates 
neural activity 
as primary 
driver of rapid 
thermal 
fluctuations. 
Table 1. Summary of reported brain temperatures across healthy, pathological, and animal models. 1225 
Note: Conditions marked with (*) represent findings from the exposed cortical surface, where absolute 1226 
temperatures are significantly lower than physiological core temperature due to evaporative cooling 1227 
(27-34°C). Thus, these terms refer to the relative thermal gradient ∆T between the tumor and 1228 
surrounding healthy parenchyma. ¹H-MRS = proton magnetic resonance spectroscopy; 3 T = 3 Tesla 1229 
magnetic field strength; IR = infrared; DWI = diffusion-weighted imaging. 1230 
 1231 
7x
14x
37x
Brain Temperature
Brain Oxygenation
Intercranial Pressure
Cerebral Blood Flow
787
5,661
10,961
28,945
activated neuron
vasodilation
astrocyte
microglia
neuron
pe
riva
scular space
arterial
blood
artery
B) A) 
free H2O diffusion in CSF
A)PRF chemical shift C) DWI
NAAH2O
chemical frequency shift
B) PRF phase shift
during HT before HT ΔT map
+ΔT
0
ΔT
monitoring temperature changes
measuring absolute
CSF temperature 
measuring absolute temperature 
restricted diffusion
in parenchymal tissue
hypertrophic microglia
atrophic
astrocytes
hyperactive
neurons
dystrophic microglia
dysfunctional
neurons
amyloid-β plaque
dila
ted s
tiff vessel dila
ted s
tiff vessel
τ-tangles
reactive
astrocytes
B) A) 
B) 
cancer cell with 
hyperactive mitochondria
A) 
necrotic core
metastasis
blood vessel
GBM
1 2
3
Brain Temperature
Metabolism Neuronal Activity
Vascular Regulation
Alzheimer’s DiseaseBrain Cancer
	Article File
	Figure 1
	Figure 2
	Figure 3
	Figure 4
	Figure 5
	Graphical Abstracta balance of heat production and removal. While the brain 122 
coordinates body temperature via thermosensitive neurons in the hypothalamus (8), 123 
its own temperature is governed primarily by local neurovascular and metabolic 124 
mechanisms (5, 9). 125 
A fundamental principle underlying these mechanisms is the tight link between the 126 
brain's immense metabolic activity and its continuous heat production. To sustain 127 
this activity and manage the resulting thermal load, the brain receives 15-20% of 128 
total cardiac output (10). While this vascular supply has traditionally been viewed as 129 
serving primarily metabolic needs, observations that resting blood flow often exceeds 130 
oxygen requirements and that the hyperemic response is largely decoupled from 131 
glucose demand suggest additional functions. One explanation for neurovascular 132 
coupling beyond metabolism is thermoregulation (11). Indeed, the cerebrovascular 133 
system acts as the brain's primary cooling mechanism. This cooling function is 134 
directly observable as a temperature gradient between the cooler arterial blood 135 
entering the brain and the warmer jugular venous blood leaving it, confirming active 136 
heat extraction (12). Crucially, this thermal gradient scales with cerebral oxygen 137 
metabolism, directly linking the heat generated by neural activity to its removal by the 138 
vasculature. While this vascular heat exchange promotes local thermal equilibrium at 139 
rest, minimizing spatial thermal gradients within the individual brain (Fig. 2A), its true 140 
importance becomes evident during the dynamic neurovascular response, which 141 
provides the cooling capacity needed to buffer the intense, localized heat from active 142 
neurons. 143 
The specifics of this dynamic adjustment are governed by neurovascular coupling. 144 
Upon neuronal activation, metabolic signaling pathways (e.g., via astrocytes) trigger 145 
vasodilation to meet energy demands (13). Because metabolic activity and heat 146 
generation are intrinsically coupled, this response concurrently manages the thermal 147 
load without requiring a dedicated thermosensor. As a result of this hyperemic 148 
response, heat removal is enhanced by cooler arterial blood acting as a heat sink. 149 
This process establishes a thermal landscape of warm microenvironments around 150 
active neurons, cooled by the adjacent arterial vasculature (Fig. 2B) (14). The 151 
magnitude of these flow responses can vary across brain regions, reflecting 152 
heterogeneous neurovascular coupling efficiency (15). 153 
Complementing these rapid vascular adjustments, cerebrospinal fluid (CSF) offers a 154 
slower, more steady-state form of thermal buffering. CSF circulates through the 155 
ventricles and perivascular spaces, helping maintain constant intracranial volume 156 
while potentially serving as a heat reservoir (16, 17). Recent work has revealed that 157 
neural activity can directly modulate CSF flow (18), potentially enhancing heat 158 
distribution across brain regions. Beyond these fluid-based mechanisms, microglia 159 
contribute to thermal homeostasis by modulating inflammatory signals that affect 160 
vascular tone, local metabolic activity, and heat production (19). This multi-161 
component system of rapid vascular responses, steady CSF circulation, and 162 
microglial modulation ensures robust temperature regulation across multiple 163 
timescales. 164 
Brain temperature follows a distinct daily rhythm and varies spatially, being coolest in 165 
the superficial cortex and warmest in deep brain structures. In humans, phantom-166 
validated MR thermometry reveals a broad effective range from 36.1°C to 40.9°C (5) 167 
(Table 1). This range reflects variation across individuals, brain regions, and 168 
physiological states: the upper extreme (40.9°C) was observed in the deep thalamus 169 
of a female participant during the luteal phase in the afternoon, while the lower 170 
extreme (36.1°C) was measured in the superficial cortical gray matter of a male 171 
participant. These variations align with daily fluctuations in metabolism and neural 172 
activity between sleep and wake states (20). However, it is critical to distinguish this 173 
wide population spread from individual physiology: within any single subject, the 174 
resting brain maintains a stable homeostatic rhythm with a narrow circadian 175 
amplitude of approximately 1°C. 176 
Importantly, the brain tolerates these slow thermal variations through compensatory 177 
mechanisms. Temperature compensation pathways, potentially mediated by cold-178 
inducible chaperone proteins, allow neural timing and circadian function to remain 179 
stable across circadian temperature fluctuations (5). However, the capacity of these 180 
homeostatic mechanisms has limits. The relationship between temperature and 181 
neural activity is bidirectional, creating a feedback loop that may become 182 
dysregulated under pathological conditions. Invasive recordings in animals 183 
demonstrate that bursts of neuronal firing increase local brain temperature by 0.1 to 184 
1.8°C within 9 to 13 seconds, well before any systemic changes in arterial blood 185 
temperature occur at approximately 39 seconds (21, 22). This temporal pattern 186 
confirms that neurons generate metabolic heat that is subsequently transferred to 187 
the vasculature. Conversely, temperature itself modulates neural function: neuronal 188 
firing rates and network oscillation frequencies increase with warming, though this 189 
effect plateaus above 39°C (23), and experimental studies show that temperature 190 
shifts of ±1°C can transiently alter neuronal excitability (24). In the hippocampus, 191 
paradoxically, both hyperthermia and small temperature decreases of 1-2°C 192 
enhance the intrinsic excitability of excitatory and inhibitory neurons (25). This 193 
creates a feedback loop: neural activity generates heat, which modulates neuronal 194 
excitability, which then affects subsequent heat production. In healthy tissue, this 195 
loop remains stable through the compensatory mechanisms described above. 196 
However, in disease states such as Alzheimer's disease (AD) or brain cancer, 197 
chronic inflammation or metabolic dysfunction may generate sustained thermal 198 
stress that overwhelms these regulatory mechanisms, potentially driving a 199 
pathological cycle of dysregulation. Astrocytes also exhibit high temperature 200 
sensitivity: mild warming to 38-39°C activates protective responses, but sustained 201 
higher temperatures cause irreversible damage and impair neurotransmitter 202 
recycling (26). 203 
Decades of invasive experiments have established the physiological foundations of 204 
brain thermoregulation, demonstrating how neuronal activity, metabolism, and 205 
vascular responses interact to maintain local thermal balance (27). Early work 206 
defined a hypothalamic proportional-control model with an adjustable set point (28), 207 
and electrophysiological studies later identified warm- and cold-sensitive neurons in 208 
the preoptic and anterior hypothalamus that integrate central and peripheral thermal 209 
inputs, providing a cellular basis for this regulation (29). Subsequent physiological 210 
and pathological investigations demonstrated that small temperature deviations can 211 
markedly influence neuronal viability, with mild hypothermia exerting neuroprotective 212 
effects and hyperthermia accelerating injury (30). More recent comparative analyses 213 
confirmed that brain temperature typically exceeds core temperature by 214 
approximately 0.4 to 2.5 °C across species (9) and behaves as a dynamic 215 
physiological signal closely coupled to neural activity and metabolism (31). However, 216 
it is crucial to note that thermoregulatory mechanisms vary across species; for 217 
instance, small rodents often exhibit distinct thermal brain-body gradients compared 218 
to primates (32), underscoring the needfor human-specific data. Together, these 219 
invasive studies elucidated the mechanistic and functional bases of cerebral 220 
thermoregulation, providing the physiological context in which non-invasive MR-221 
based temperature measurements in humans can now be interpreted. 222 
Despite these robust regulatory mechanisms, the brain's capacity for thermal 223 
homeostasis is not unlimited. When the interplay between metabolism, perfusion, 224 
and heat dissipation is compromised, local temperatures can deviate from the 225 
optimal window, leading to states of pathological hyperthermia or hypothermia. In 226 
this neurophysiological context, these terms refer not necessarily to systemic fever 227 
or clinical hypothermia, but to sustained deviations from the local homeostatic 228 
baseline in the form of spatial gradients or temporal shifts that are sufficient to alter 229 
neuronal excitability, metabolism, or protein kinetics. These deviations represent 230 
internal thermal extremes whose impact on neural function is particularly relevant in 231 
conditions such as neurodegenerative diseases and brain tumors, a topic explored in 232 
Section 4. 233 
 234 
3 Brain thermometry 235 
Accurate brain temperature measurements are essential to our understanding of 236 
thermoregulatory mechanisms and their influencing factors. Invasive techniques, 237 
such as thermocouples or thermistors, provide direct measurements but are limited 238 
to surgical and intensive care settings in humans. Similarly, surface-sensitive 239 
methods, such as intraoperative infrared thermometry, are restricted to exposed 240 
brain surfaces and are impractical for deep brain measurements (33). 241 
Magnetic Resonance (MR)-based thermometry is a promising non-invasive 242 
approach for brain temperature measurement, offering the advantage of estimating 243 
temperatures in deep brain regions. Proton Resonance Frequency (PRF) chemical 244 
shift thermometry using proton MR Spectroscopy (1H-MRS) allows for absolute 245 
temperature measurement by exploiting the linear relationship between temperature 246 
and the resonance frequency of water protons. Most commonly, the temperature-247 
independent N-acetylaspartate (NAA) peak is used as a reference to the position of 248 
the water peak (Fig. 3A) (34). Table 1 provides an overview of reported brain 249 
temperatures obtained using these methods. However, accurate results depend on 250 
strict calibration protocols. It has been demonstrated that applying generic literature 251 
calibration values to a specific scanner setup can lead to baseline offsets exceeding 252 
1.0°C, underscoring the necessity of validating calibration parameters for the specific 253 
scanner setup (35). Furthermore, tissue heterogeneity (e.g., protein content) exerts a 254 
secondary influence on calibration. While theoretical models in pure water suggest 255 
protein-driven shifts could be substantial (36), investigations using physiological fluid 256 
mimics indicate these effects are significantly dampened in the biological 257 
environment. It has been shown that for typical physiological protein variations, the 258 
resulting temperature error ranges from 0.1°C to 0.4°C (37). A recent validation study 259 
employing simultaneous invasive optical probes and MRS confirms that when 260 
calibration parameters are validated for the specific scanner environment, the 261 
method achieves high accuracy (human cohorts, as well as animal 318 
models. 319 
4.1 Vascular, metabolic, and thermoregulatory disruptions in AD 320 
AD is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles 321 
composed of hyperphosphorylated tau (τ) protein, leading to neuronal loss, brain 322 
atrophy and cognitive decline (49). The aggregation of Aβ commences in a 323 
prolonged pre-symptomatic phase, up to 20 years before dementia clinically 324 
manifests (50). Cardiovascular health markers are directly linked to Aβ deposition 325 
(51), and hypertension is recognized as a modifiable risk factor for late-life cognitive 326 
impairment and dementia (52). Age-related vascular function alterations, such as 327 
increased vessel stiffness (53), vessel dilation (54) and reduced blood flow 328 
responsivity (55) contribute to the pathophysiology. Neurovascular uncoupling, 329 
where CBF fails to meet dynamic metabolic demands, is implicated in early cognitive 330 
impairment (56) and AD (57, 58). This breakdown of neurovascular coupling impairs 331 
the brain's primary cooling mechanism described in Section 2, where CBF normally 332 
provides rapid heat removal from metabolically active regions. The thermal 333 
consequences of this impairment, specifically how much brain temperature actually 334 
changes and whether this drives disease progression, remain poorly understood and 335 
represent a critical knowledge gap. 336 
Vascular insufficiency frequently leads to chronic hypoxia, which exacerbates 337 
oxidative stress and neuroinflammation, accelerating neuronal damage and cognitive 338 
decline (59). Neuroinflammation itself can elevate both regional and global brain 339 
temperatures through increased microglial metabolic activity (60–62). This creates a 340 
potential feed-forward loop where elevated temperatures further activate 341 
inflammatory pathways, as demonstrated by human cell culture studies showing that 342 
even a 2°C rise enhances microglial neurotoxicity and inflammatory mediator release 343 
(63), which in turn generate more heat through enhanced cellular metabolism, 344 
overwhelming the compromised cooling capacity. While chronic neuroinflammation 345 
may initially be protective, microglial activation coincides with early Aβ deposition 346 
(64), transitioning from hypertrophic microglia in early disease phases to dystrophic 347 
microglia dominating later stages (65). Astrocytes similarly undergo distinct changes: 348 
initially atrophic, then transitioning into reactive states, including both neuroprotective 349 
and pro-inflammatory phenotypes (66). Microglial activation in particular is 350 
associated with increased glucose uptake and metabolic activity (67). Increased 351 
metabolic activity has been observed in healthy older adults (68) and early cognitive 352 
impairment (69), possibly as a compensatory response (70). In addition, neural 353 
hyperactivity has been observed in cognitively normal older people with varying 354 
levels of AD pathology (71) and early AD (72). This hyperactivity often manifests as 355 
subclinical epileptiform activity or "silent" hippocampal seizures, which were detected 356 
in 42% of AD patients without a history of seizures and are associated with 357 
accelerated cognitive decline (73). Mechanistically, this has been proposed to arise 358 
from the early degeneration of inhibitory interneurons, leading to circuit 359 
hyperexcitability (74). This neuronal firing, combined with inflammatory heat 360 
production, likely generates a metabolic heat load that exceeds the dissipation 361 
capacity of the already impaired vascular system. This is consistent with the thermal 362 
framework we propose below: even modest chronic temperature elevations may 363 
produce sustained, moderate hyperexcitability sufficient to generate subclinical 364 
epileptiform discharges, rather than the acute, large-magnitude thermal transients 365 
required to trigger overt seizure activity. In contrast, glucose metabolism declines in 366 
the later stages of AD (75–77), revealing a progression from early hypermetabolism 367 
to late-stage hypometabolism. 368 
Given temperature's established influence on neuronal excitability and astrocyte 369 
function (24, 26), these metabolic and inflammatory changes likely have thermal 370 
consequences. Crucially, elevated temperatures within the physiological range have 371 
been explicitly linked to increased Aβ production (78), accelerating amyloid fibrillation 372 
(79), and leading to more compact amyloid plaque structures and progressive Aβ 373 
accumulation (80), caused by the exothermic nature of spontaneous Aβ fibril 374 
formation (81). Impaired vascular pulsation may exacerbate this vicious cycle by 375 
hindering Aβ clearance (82, 83) and further compromising CSF-mediated heat 376 
distribution, another key thermoregulatory mechanism identified in Section 2. 377 
Poor sleep in older adults, known to disrupt systemic and brain thermoregulation (84, 378 
85), is associated with increased Aβ accumulation (86) and worse overall brain 379 
health (87). Sleep disruption may particularly impair the nocturnal peak in CBF and 380 
the temperature nadir described in Section 2, further destabilizing thermal 381 
homeostasis. Conversely, τ pathology has been associated with lower temperatures. 382 
Lower body temperature correlates with increased tau pathology in cognitively 383 
normal older adults (88), and experimental hypothermia increases τ levels (89). 384 
Additionally, τ phosphorylation exhibits circadian variations linked to body 385 
temperature and sleep rhythms (90). Mild hyperthermic interventions such as sauna 386 
bathing have demonstrated potential in reducing τ phosphorylation and dementia risk 387 
(91). 388 
Based on these converging but indirect observations, we propose a theoretical 389 
framework for temperature changes across AD stages (Fig. 4). In this context, we 390 
define 'hyperthermia' not as clinical pyrexia, but as a chronic, low-grade elevation 391 
(estimated +0.5–1.0°C) above the individual's homeostatic baseline, consistent with 392 
the temperature-dependent scaling of amyloid fibrillation observed in vitro (79). 393 
Thermodynamic studies indicate that even such modest, sustained elevations are 394 
sufficient to significantly accelerate temperature-dependent pathological processes, 395 
specifically amyloid fibrillation and tau phosphorylation (78, 90). Recent analyses 396 
suggest this creates a 'vicious cycle' where aggregation-induced thermogenesis 397 
further promotes protein accumulation (45). We propose that elevated temperature 398 
acts as a thermodynamic catalyst for this molecular cascade, amplifying pathological 399 
protein dynamics, driven by neuronal hyperactivity, hypertrophic microglia, reactive 400 
astrocytes, and enhanced Aβ production, which together characterize the pre-401 
symptomatic phase of AD (Fig. 4A). In contrast, later-stage AD, marked by extensive 402 
tau pathology, neuronal dysfunction, dystrophic microglia, reduced metabolic activity, 403 
and increased vascular stiffness and dilation, likely shifts towards hypothermal 404 
conditions (Fig. 4B). Recent clinical evidence supports the late-stage component of 405 
this framework: DWI-based thermometry has revealed that ventricular CSF 406 
temperature is significantly lower (−0.5°C) in patients with AD compared to age-407 
matched healthy controls (Table 1, 92). This global cooling likely results from 408 
impaired heat generation due to disrupted glucose metabolism (75). This model 409 
suggests that AD represents a progressive failure of thermoregulatory homeostasis, 410 
where normal heat dissipation mechanisms through CBF and CSF circulation cannot 411 
compensate for early-stage metabolic and inflammatory heat generation, ultimately 412 
leading to the observed hypothermal dysfunction in later stages. While the early-413 
stage hyperthermia remains speculative and the complete framework requires414 
longitudinal temperature measurements for validation, it provides testable predictions 415 
for understanding temperature's role in AD progression and could potentially inform 416 
biomarker development and therapeutic strategies. 417 
4.2 The role of temperature in the biology of brain cancer 418 
4.2 Thermal profiles and temperature dysregulation in brain tumors 419 
While neurodegenerative processes in AD may lead to temperature dysregulation 420 
over decades, brain tumors present a different temporal and spatial pattern of 421 
thermal disruption. We focus on gliomas and intracranial metastases, as gliomas 422 
represent the most common primary malignant brain tumors and metastases the 423 
most common intracranial tumors overall. 424 
Brain tumors, particularly glioblastoma (GBM), profoundly alter their 425 
microenvironment, primarily in response to metabolic and vascular constraints. One 426 
well-established driver of these changes is hypoxia, which arises when rapid tumor 427 
expansion outpaces vascular supply (93, 94). Tumors respond by upregulating 428 
angiogenesis (95) and engaging surrounding astrocytes to sustain tumor survival 429 
and proliferation. Unlike the organized neurovascular coupling that normally 430 
maintains thermal homeostasis (described in Section 2), these tumor blood vessels 431 
are structurally and functionally aberrant (96). They respond chaotically to metabolic 432 
demands, failing to provide efficient heat exchange and instead creating thermal 433 
gradients that may influence tumor behavior. 434 
Although comprehensive temperature mapping in human brain tumors remains 435 
limited, comparing intraoperative thermometry (IIT), e.g., intraoperative infrared (IR) 436 
thermometry, with non-invasive MRS reveals a complex thermal landscape where 437 
absolute temperatures depend heavily on measurement conditions, yet relative 438 
patterns consistently reflect tumor biology (Table 1). Intracranial metastases illustrate 439 
how tumor histology drives thermal profiles. Even under identical open-surgical 440 
conditions, metastatic lesions exhibit diverging thermal signatures based on their 441 
vascular architecture. Highly vascularized melanoma metastases typically present as 442 
hyperthermic (∆T > +0.5°C), likely due to sustained metabolic heat generation and 443 
dense perfusion (97). This thermal profile aligns with perfusion MRI evidence 444 
demonstrating that melanoma metastases possess significantly higher capillary 445 
permeability and plasma volume compared to other histologies (98). In contrast, lung 446 
adenocarcinoma metastases have been observed as significantly hypothermic (∆T ≈ 447 
-3.5°C) (99), consistent with their comparative hypovascularity and lower perfusion 448 
density (98). This stark contrast within the same modality demonstrates that intrinsic 449 
tumor biology, specifically the balance between metabolic heat generation and 450 
vascular density, can overcome or exacerbate environmental thermal effects. 451 
In gliomas, a similar thermal hierarchy correlates with malignancy, though the 452 
absolute values are method-dependent. High-grade glioblastomas (GBM) 453 
consistently present as the "coldest" glioma phenotype. In IIT studies, GBMs appear 454 
significantly hypothermic relative to the surrounding parenchyma (∆T ≈ -2.2°C). This 455 
is attributed to their characteristic necrotic cores, which lack metabolic activity and 456 
act as thermal voids (Fig. 5A) (99). Low-grade gliomas, conversely, appear relatively 457 
"warmer" than their high-grade counterparts, though their absolute presentation 458 
varies by technique. 459 
This methodological divergence in low-grade gliomas highlights the impact of the 460 
measurement environment. In pediatric closed-skull MRS studies, low-grade gliomas 461 
appear hyperthermic (∆T ≈ +0.7°C) (100). This likely reflects the retention of 462 
metabolic heat from tumor proliferation within the closed cranium (additionally, 463 
pediatric patients exhibit higher baseline brain metabolism, which may amplify this 464 
effect). However, in adult open-skull IIT studies, low-grade gliomas often appear 465 
hypothermic relative to healthy tissue, though still warmer than GBMs. This shift to 466 
hypothermia in the surgical setting is likely driven by evaporative cooling: the chaotic, 467 
inefficient tumor vasculature fails to re-warm the exposed tissue as rapidly as the 468 
robustly perfused healthy cortex. General anaesthesia is also known to suppress 469 
thermoregulation and reduce core body temperature (101), which may further 470 
contribute to lower absolute temperature readings in intraoperative studies. Thus, 471 
while the absolute temperature flips between methods (Hot in MRS vs. Cold in IIT), 472 
the biological signal remains consistent: proliferative low-grade lesions display higher 473 
thermal energy than necrotic high-grade lesions. 474 
A primary driver of these thermal shifts may be the high metabolic activity of tumor 475 
cell mitochondria. According to the Warburg effect (102), many cancer cells prefer 476 
glycolysis, which is a faster but less efficient way of generating energy, even when 477 
oxygen is present. However, recent findings show that mitochondria in cancer cells 478 
remain highly active and generate considerable heat (Fig. 5B). Resected human 479 
tumor samples reveal that mitochondria in cancer cells can operate at significantly 480 
higher temperatures than those in healthy tissue (103), suggesting that oxidative 481 
phosphorylation continues in parallel with glycolysis. This intense metabolic activity 482 
may push mitochondria beyond normal physiological limits (104), contributing directly 483 
to elevated temperatures in metabolically active tumor regions. The heat generated 484 
by this hypermetabolism likely exceeds the capacity of normal thermoregulatory 485 
mechanisms, particularly given the compromised vascular architecture. 486 
Paradoxically, this hypothermic presentation observed in GBMs occurs despite these 487 
metabolically hyperactive cells. This apparent contradiction is likely driven by tumor 488 
architecture. In GBM, the characteristic necrotic core lacks metabolic activity, acting 489 
as a "thermal void" that overrides the heat generated by the hyperactive peritumoral 490 
rim (Fig. 5A). This stands in contrast to the hyperthermia observed in low-grade 491 
gliomas and melanoma metastases, which typically lack extensive necrosis and 492 
maintain dense vascularity. Thus, rather than a uniform "hot spot," the thermal 493 
gradient serves as a functional biomarker for tumor viability, distinguishing active 494 
proliferation from necrosis. 495 
Beyond intrinsic metabolic and vascular factors, the tumor microenvironment is 496 
shaped by complex cellular interactions that drive disease progression (Fig. 5A). The 497 
inset illustrates three critical mechanisms: activated astrocytes promoting tumor 498 
proliferation through direct cell-cell contacts, neurons releasing signaling factors that 499 
facilitate tumor cell invasion, and irregular, leaky blood vessels that fail to regulate 500 
heat exchange (105–109). Given the temperature sensitivity of these cellular 501 
interactions, particularly synaptic transmission and metabolic processes, localized 502 
thermal shifts in the tumor microenvironment could modulate these multi-layered 503 
glioma-neuron networks, adding another dimension to disease progression. 504 
Cancer cells themselves are inherently temperature-sensitive and can undergo 505 
stress responses or cell death when exposed to elevated thermal levels (110). 506 
However, this sensitivity varies considerably across GBM cell populations: 507 
thermosensitive subpopulations undergo cell death at fever-range temperatures, 508 
while thermotolerant subpopulations activate protective stress responses that confer 509 
a survival advantage under the same conditions (111). Endogenous thermal 510 
gradients inthe tumor microenvironment may therefore act as a selective pressure 511 
favoring thermotolerant subpopulations, potentially contributing to phenotypic drift 512 
and treatment resistance over time. Rather than being a passive consequence of 513 
metabolism, temperature may actively shape tumor progression. Understanding 514 
these thermal interactions might offer novel insights into brain tumor adaptation 515 
mechanisms and suggest innovative therapeutic avenues. 516 
5 Broader implications and outlook 517 
The next decade will likely see brain temperature transform from an overlooked 518 
parameter to a central consideration in neurology. Three converging forces make this 519 
shift inevitable: our expanding ability to non-invasively monitor brain temperature, 520 
mounting evidence that thermal dysregulation drives disease progression, and the 521 
urgent need to understand thermal limits as our planet warms. Each of these 522 
domains (clinical, technological, and environmental) offers both immediate 523 
opportunities and profound challenges. 524 
Clinical Frontiers: From Observation to Intervention 525 
If brain temperature changes indeed characterize different disease stages as 526 
hypothesized, this would open new diagnostic and therapeutic possibilities. While we 527 
have documented temperature alterations in neurological diseases, understanding 528 
their functional impact remains a critical gap. In Alzheimer's disease, the proposed 529 
progression from early hyperthermia to late-stage hypothermia could provide staging 530 
biomarkers and therapeutic targets. Similarly, the distinct thermal signatures of brain 531 
tumors, with hypothermic glioblastomas contrasting with hyperthermic metastases, 532 
may soon guide treatment decisions. MR-based thermometry could replace 533 
expensive methods like [18F]-fluoroethyltyrosine PET for assessing post-treatment 534 
metabolic activity, providing a non-invasive, cost-effective alternative for monitoring 535 
treatment response. 536 
The COVID-19 pandemic has unexpectedly expanded this clinical frontier. 537 
Inflammatory changes following severe infection (112), coupled with elevated brain 538 
temperatures after even mild COVID-19 (113), reveal complex thermal responses to 539 
viral insults. As research explores links between COVID-19, neuroinflammation, and 540 
dementia risk (114–116), brain temperature monitoring could illuminate post-541 
infectious neurodegenerative processes. This convergence of infection, 542 
inflammation, and temperature dysregulation may represent a broader pattern 543 
relevant to other neurotropic pathogens, warranting systematic investigation. 544 
Therapeutic Temperature Modulation: Precision and Peril 545 
Temperature is emerging as both a therapeutic tool and a critical safety parameter. 546 
MR-compatible thermal therapies like laser interstitial thermal therapy and high-547 
intensity focused ultrasound already leverage real-time PRF thermometry for treating 548 
brain tumors (39). However, promising non-MR-compatible approaches, such as 549 
magnetic nanoparticle-mediated hyperthermia, present new challenges. This 550 
technique has shown tumor suppression in animal models (117, 118) and survival 551 
benefits in recurrent GBM patients (119, 120), yet lacks real-time temperature 552 
monitoring. Computational modelling offers a path forward: while whole-brain 553 
temperature has been successfully modelled in healthy humans (121, 122) and 554 
ischemic stroke (123), extending these models to brain cancer pathology remains an 555 
important gap. Developing tumor-specific thermal models that integrate nanoparticle 556 
heating dynamics (124) could enable safer application of non-MR-compatible 557 
thermal therapies. 558 
Beyond therapeutic heating, temperature modulation is revealing unexpected 559 
neuromodulatory potential. Focused ultrasound achieves neural inhibition partly 560 
through thermal mechanisms (125), while transcranial magnetic stimulation deposits 561 
thermal energy that may contribute to its effects (126). Even infrared stimulation 562 
appears to modulate neural activity through temperature-dependent pathways (127). 563 
These discoveries suggest temperature could become a precise tool for non-invasive 564 
brain modulation, but only if we understand the thresholds between therapeutic 565 
effect and thermal damage. This knowledge gap becomes particularly concerning 566 
given the widespread clinical adoption of these technologies. 567 
Environmental Extremes: The Approaching Crisis 568 
Perhaps most urgently, climate change is creating an unprecedented natural 569 
experiment in human thermal tolerance. With 30% of the global population already 570 
experiencing dangerous heat exposure for at least 20 days annually (128), and this 571 
figure rising inexorably, understanding brain thermal limits is no longer academic but 572 
essential for public health. Heat exposure disrupts motor control and cognitive 573 
function (129), with emerging evidence linking heatwaves to increased neural 574 
excitability (130). These acute effects may be especially dangerous for individuals 575 
with compromised thermoregulation due to aging or neurological disease (131). 576 
The intersection of environmental heating and disease-related thermal dysregulation 577 
represents a particularly vulnerable convergence. Alzheimer's patients with impaired 578 
thermoregulation facing extreme heat events, brain tumor patients undergoing 579 
thermal therapy during heatwaves, or individuals with post-COVID 580 
neuroinflammation experiencing temperature extremes: these scenarios demand 581 
immediate research attention. Understanding these compound thermal challenges 582 
will be crucial for protecting vulnerable populations as extreme weather events 583 
become more frequent (132–134). 584 
Charting the Path Forward 585 
Brain temperature sits at the nexus of metabolism, perfusion, and neural function, 586 
representing fundamental processes that determine cognitive capacity and survival. 587 
Yet we've barely begun mapping this thermal landscape. Critical questions emerge 588 
from this synthesis: Does the hypothesized temperature trajectory in AD (early 589 
hyperthermia transitioning to late hypothermia) represent a universal pattern or 590 
distinct thermal phenotypes? Why do metabolically active GBMs paradoxically 591 
exhibit hypothermia? Can refined MR thermometry resolve the aging temperature 592 
controversy and provide early disease biomarkers? How do temperature gradients 593 
influence the complex neuron-tumor interactions we're only beginning to 594 
understand? And perhaps most urgently, do individuals with compromised 595 
thermoregulation from neurological disease face compounded vulnerability to 596 
environmental heat stress? 597 
The tools to answer these questions are emerging. Advanced MR thermometry 598 
techniques promise unprecedented insights into brain thermal dynamics. Combined 599 
with our growing understanding of the molecular mechanisms linking temperature to 600 
neural function, we stand poised for breakthrough discoveries. But progress requires 601 
recognizing brain temperature as more than a passive indicator: it's an active 602 
participant in health and disease, deserving dedicated research programs and 603 
clinical attention. 604 
As environmental stressors intensify, therapeutic applications expand, and our 605 
population ages, understanding brain thermoregulation transitions from scientific 606 
curiosity to urgent necessity. The brain's thermal future will be shaped by how quickly 607 
we can map its thermal present. This review calls for coordinated efforts across 608 
disciplines, from basic neuroscience to climate science, to ensure we're prepared for 609 
the thermal challenges ahead. Our cognitive future may literally depend on keeping 610 
our cool. 611 
Supplemental Material 612 
The detailed search methodology, queries, and results usedto generate the 613 
publication counts for Figure 1 are available at: 614 
https://doi.org/10.6084/m9.figshare.31549891 615 
Acknowledgments 616 
Preprint is available at https://osf.io/preprints/osf/pkwh7 617 
Disclosures 618 
No conflicts of interest, financial or otherwise, are declared by the authors. 619 
Grants 620 
This work was supported by the Mark Hughes Foundation Centre for Brain Cancer 621 
Research through the Garry Willgoose PhD Scholarship, and by Tour de Cure 622 
Australia through a PhD Support Scholarship, both awarded to C.B. 623 
Author contributions 624 
C.B. and A.B. drafted manuscript. C.B. prepared figures. C.B., A.B, M.F, S.R and 625 
M.B. edited and revised manuscript. C.B., A.B, M.F, S.R. and M.B. approved final 626 
version of manuscript. 627 
 628 
 629 
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