Cerebral Temperature Dysregulation: MR Thermographic Monitoring in a Nonhuman Primate Study of Acute Ischemic Stroke

Abstract

Background and Purpose Cerebral thermoregulation remains poorly understood. Temperature dysregulation is deeply implicated in potentiation of cerebrovascular ischemia. We present a multi-phasic, MR thermographic study in a non-human primate (NHP) model of MCA infarction, hypothesizing detectable brain temperature disturbances and brain-systemic temperature decoupling. Materials and Methods Three rhesus macaque NHP were sourced for three-phase MRI: 1) baseline MRI (t-7); 2) seven-hour continuous MRI following minimally-invasive, endovascular MCA stroke induction (t0); 3) post-stroke day MRI (t1) follow-up. MR thermometry was achieved by multi-voxel spectroscopy (semi-LASER MRSI) using the proton resonance frequency chemical shift. Relationship of brain and systemic temperatures with time and infarction volumes was characterized using a mixed-effects model. Results Following MCA infarction progressive cerebral hyperthermia was observed in all three subjects, significantly outpacing systemic temperature fluctuations. Highly significant associations were observed for systemic, hemispheric, and global brain temperatures (F-stat p.0005 for all regressions) relative to time from stroke induction. Significant differences in the relationship between temperature and time following stroke onset were detected when comparing systemic temperatures with ipsilateral (p=.007), contralateral (p=.004), and infarction core (p=.003) temperatures following multiple comparisons correction. Significant associations were observed between infarction volumes and both systemic (p≤.01) and ipsilateral (p=.04) brain temperatures, but not contralateral brain temperature (p=.08). Conclusion Successful physiologic and continuous post-ischemic cerebral MR thermography was conducted, and prescribed in an NHP infarction model to facilitate translatability. The results confirm hypothesized temperature disturbance and decoupling of physiologic brain-systemic temperature gradients. These findings inform a developing paradigm of brain thermoregulation, and the applicability of brain temperature as a neuroimaging biomarker in CNS injury.

Simian immunodeficiency virus transiently increases brain temperature in rhesus monkeys: detection with magnetic resonance spectroscopy thermometry

“…Although rectal temperatures predicted and thus could serve as surrogate markers for brain temperatures in SIV‐infected monkeys under the conditions we studied, brain temperatures do not always correlate with peripheral temperature measures . Thus, brain temperature can be a useful independent measure and could be informative in other brain disorders, including in major depression, which is associated with inflammation, as well as in addiction disorders, psychotic disorders, seizure disorders, and stroke …”

The Brain Thermal Response as a Potential Neuroimaging Biomarker of Cerebrovascular Impairment

“…MR chemical shift thermometry, exploiting the temperature-dependent difference between water and the methyl proton resonance of NAA, was chosen to approximate temperature using an optimized protocol previously reported for phantom as well as human and non-human primate in vivo thermometry. 19, 24, 25, 33 The present study takes advantage of the unique pathophysiologic attributes of chronic cerebrovascular ischemia, in a cohort allowing multiphasic interrogation of a flow-temperature relationship which may not be pragmatic in the clinical acute stroke setting. Ishigaki et al previously reported the use of PET combined with localized, single-voxel MRS-based thermometry to explore the relationship of brain temperature in steno-occlusive disease, observing positive correlations between brain temperature difference (ipsilateral–contralateral hemisphere) with both CBV and OEF.…”

“…This difference may in part reflect that baseline brain temperature is inherently a known indicator of diseased tissue energetics, with higher temperature associated positively with hypoperfusion and ischemia. 16, 19, 36–38 The benefit of BTR is the ability to quantify a maneuver response, thus producing a form of physiologic contrast with the potential for characterizing not only static tissue impairment, as with baseline brain temperatures, but also the dynamics of the hemodynamic response in a manner similar to CVR. The overall quadratic relationships suggest the presence of multiple regimes of temperature (dys)regulation across the brain determined by additional hemodynamic parameters such as OEF and CMRO 2 .…”

“…19, 24, 25 Temperature analysis and localization of the grid onto CVR maps was performed using in-house software written in Matlab (Mathworks, version 2015a). Specifically, absolute temperature was calculated using the difference between water and N -acetylaspartate (NAA) proton resonance frequencies and the relationship −0.01 ppm/°C.…”

“…13, 14 Increased brain and systemic temperatures strongly potentiate ischemic injury due to the high sensitivity of neuronal substrate to even small temperature fluctuations. 15–19 Cerebral thermoregulation remains poorly understood, owing to historically limited methodologies consisting of highly invasive and costly implantable probes. Past study has thus relied primarily on animal models or used systemic temperature as a surrogate for brain temperature, with limited empirical exploration of the effect of hemodynamic impairment on thermal dynamics.…”