The study of brain temperature is important for a number of clinical conditions such as stroke, traumatic brain injury, schizophrenia and birth asphyxia (for neonates). A direct method to estimate brain temperature non-invasively will allow assessment of brain thermoregulation and its variation in clinical conditions. Magnetic resonance imaging is a powerful technique widely used for diagnosis of a range of neurological conditions. All magnetic resonance procedures involve manipulation of the hydrogen nuclei in the water molecules of the human body. The resonance frequency of the water molecules is temperature dependent, thus MR thermometry is a powerful tool for non-invasive temperature measurement. Using internal reference MR spectroscopic imaging (MRSI), absolute brain temperature maps can be estimated. However a number of temperature independent factors influence MRSI data acquisition, thus a thorough validation is necessary and is the focus of this PhD study. In this PhD study using phantom (test object) studies it was shown that optimization of the MRSI pulse sequence is necessary to reduce systematic error in temperature maps and extensive in-vitro validation of MRSI temperature mapping was performed. A custom made temperature-controlled phantom was designed for this purpose and is presented in this thesis. MRSI data acquired from healthy (young and elderly) volunteers was employed to assess regional brain temperature variations and repeatability. Finally, the feasibility of employing fast echo planar spectroscopic imaging for volumetric MRSI temperature mapping will be presented in this thesis.

Increased temperature is common after brain trauma and stroke, considered to be detrimental to outcome and usually treated with systemic cooling interventions. However, targeting cooling interventions at the head may be more logical. In addition to arterial blood, the human brain is cooled by heat loss through the skull and heat loss from the upper airways. It is these two mechanisms of heat loss which are the subject of this thesis. The initial research aim was to find out if restoring ‘normal’ airflow through the upper respiratory tracts of intubated, brain-injured patients could reduce brain temperature. Air at room temperature and humidity replicating normal resting minute volume was continuously administered nasally to 15 such patients. After a 30 minute baseline, they were randomised to receive airflow or no airflow for 6 hours and then crossed over for a further 6 hours. The airflow did not produce significant reductions in intracranial temperature (Mean -0.13 °C, SD 0.55 °C, 95% CI -0.43 to 0.17 °C). However, some evidence of heat loss through the skull was serendipitously observed. This was investigated formally in a randomised factorial trial, together with nasal airflow with enhancements (unhumidified air at twice minute volume with 20 ppm nitric oxide gas) intended to overcome some of the possible reasons for the neutral results with ‘normal’ airflow. After a 30 minute baseline, 12 intubated, brain-injured patients received enhanced nasal airflow, bilateral head fanning (8 m/s), both together and no intervention in randomised order. Each intervention was delivered for 30 minutes followed by 30 minutes washout. Mean brain temperature was reduced by 0.15 °C with nasal airflow (p=0.001, 95% CI 0.06 to 0.23 °C) and 0.26 °C with head fanning (p<0.001, 95% CI 0.17 to 0.34 °C). The estimate of the combined effect of airflow and fanning on brain temperature was 0.41 °C. Physiologically, this study demonstrated that heat loss through the upper airways and through the skull can reduce parenchymal brain temperature in brain-injured humans, that the effects are additive and the onset of temperature reduction is rapid. The most promising mechanism appeared to be heat loss through the skull and the final piece of research involved developing and initial (phase I) assessment of a convective head cooling device in healthy volunteers, with intracranial temperature measured non-invasively by magnetic resonance spectroscopy. After a 10 minute baseline, five healthy volunteers received 30 minutes head cooling followed by 30 minutes head and neck cooling via a hood and neck collar delivering 14.5 °C air at 42.5 L/s. The net brain temperature reduction with head cooling was 0.45 °C (SD 0.23 °C, p=0.01, 95% CI 0.17 to 0.74 °C) and with head and neck cooling 0.37 °C (SD 0.30 °C, p=0.049, 95% CI 0.00 to 0.74 °C). There was no significant reduction in cooling with progressive depth into the brain i.e. core brain was cooled. The main relevance of this research is physiological because it adds to knowledge and understanding of mechanisms of heat loss from the upper airways and through the skull in humans. Clinically, factors which enhance or inhibit these mechanisms may have an effect on brain temperature but the therapeutic relevance of head cooling by these methods requires further research.

Regional tissue temperature dynamics in the brain are determined by the balance of the metabolic heat production rate and heat exchange with blood flowing through capillaries embedded in the brain tissue, the surrounding tissues and the environment. Local changes in blood flow and metabolism during functional activity can upset this balance and induce transient temperature changes. Invasive experimental studies in animal models have estab- lished that the brain temperature changes during functional activity are observable and a definitive relationship exists between temperature and brain activity. We present a theoreti- cal framework that links tissue temperature dynamics with hemodynamic activity allowing us to non-invasively estimate brain temperature changes from experimentally measured blood- oxygen level dependent (BOLD) signals. With this unified approach, we are able to pinpoint the mechanisms for hemodynamic activity-related temperature increases and decreases. In addition to these results, the potential uses and limitations of optical measurements are dis- cussed.

The controlled lowering of core body temperature to 32°C to 34°C is defined as therapeutic hypothermia (TH). Therapeutic hypothermia has been shown to improve neurological outcome and survival in unconscious patients successfully resuscitated after cardiac arrest. Brain temperature is important for cerebral protection therefore methods for primarily cooling the brain have also been explored. This thesis focuses on the likelihood that intranasal cooling can induce, maintain and control cerebral hypothermia. The method uses bilaterally introduced intranasal balloons circulated with cold saline. Selective brain cooling induced with this method was effectively accomplished in pigs with normal circulation while no major disturbances in systemic circulation or physiological variables were recorded. The temperature gradients between brain and body could be maintained for at least six hours. Intranasal balloon catheters were used for therapeutic hypothermia initiation and maintenance during and after successful resuscitation in pigs. Temperature reduction was also obtained by combined intranasal cooling and intravenous ice-cold fluids with possible additional benefits in terms of physiologic stability after cardiac arrest. Rewarming was possible via the intranasal balloons. In these studies brain temperature was recorded invasively by temperature probes inserted in the brain. The fast changes in pig’s brain temperature could also be tracked by a non-invasive method. High-spatial resolution magnetic resonance spectroscopic imaging (MRSI) without internal reference showed a good association with direct invasive temperature monitoring. In addition the mapping of temperature changes during brain cooling was also possible. In awake and unsedated volunteers subjected to intranasal cooling brain temperature changes were followed by two MR techniques. Brain cooling was shown by the previously calibrated high-spatial resolution MRSI and by the phase-mapping method. Intranasal cooling reduced body temperature slightly. The volunteers remained alert during cooling, the physiological parameters stable, and no shivering was reported.