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 the potentiation of cerebrovascular ischemia. We present a multiphasic, MR thermographic study in a nonhuman primate model of MCA infarction, hypothesizing detectable brain temperature disturbances and brain-systemic temperature decoupling.

Materials and methods: Three Rhesus Macaque nonhuman primates were sourced for 3-phase MR imaging: 1) baseline MR imaging, 2) 7-hour continuous MR imaging following minimally invasive, endovascular MCA stroke induction, and 3) poststroke day 1 MR imaging follow-up. MR thermometry was achieved by multivoxel spectroscopy (semi-localization by adiabatic selective refocusing) by using the proton resonance frequency chemical shift. The relationship of brain and systemic temperatures with time and infarction volumes was characterized by using a mixed-effects model.

Results: Following MCA infarction, progressive cerebral hyperthermia was observed in all 3 subjects, significantly outpacing systemic temperature fluctuations. Highly significant associations were observed for systemic, hemispheric, and global brain temperatures (F-statistic, P = .0005 for all regressions) relative to the 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).

Conclusions: Successful physiologic and continuous postischemic cerebral MR thermography was conducted and prescribed in a nonhuman primate 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.

Fig 1.

MR thermographs in subject 3 obtained during t⁻⁷ (A) and t⁰ (B) sessions, overlaid on T1-MPRAGE images. Terminal DWI (C) obtained at the conclusion of the t⁰ session following endovascular stroke induction demonstrates a large MCA territory infarction. Thermographs in A and B are presented in equivalent color scales, depicting voxelwise brain versus systemic temperature gradients. Disturbance to the geographic distribution of brain temperature gradients present during physiologic t⁰ conditions are present, with notable, diffuse cerebral hyperthermia affecting both hemispheres in B. Generalized cerebral heating following infarction corresponds to significant elevation above decoupled systemic temperatures (not shown) as a function of time and infarction volume (see text).

Fig 2.

Subject-specific absolute temperature versus time for paired prestroke and stroke sessions. For each subject, the vertical columns represent t⁰ above and t⁻⁷ below. The y-axis in t⁰ plots represents MR imaging–derived temperatures for the hemisphere ipsilateral and contralateral to the infarction, as well as systemic temperatures. All plots are presented in the same vertical scale, with errors bars (SD) as indicated. The final time point in all t⁰ plots represents values from the poststroke session. Progressive heating of both cerebral hemispheres is present in all 3 subjects, outpacing the progressive systemic febrile temperatures in stroke aftermath. Brain hyperthermia is noted to resolve in the t¹ session for all subjects. By comparison, all baseline t⁻⁷ scans exhibit closely coupled brain systemic temperatures, despite fluctuations related to early postanesthetic hypothermia during subject preparation.

Fig 3.

Aggregated fit from individual regressions from each subject, depicted for systemic temperatures, average hemispheric temperature ipsilateral and contralateral to infarction, and those voxels defined within the infarction territory. Individual regressions derived from a linear fixed-effects model demonstrate highly significant associations among all variables relative to time, as well as significant differences between brain temperatures and systemic temperatures following multiple-comparison correction (Table 2).

Fig 4.

Subject-specific histograms of hemispheric cerebral temperature versus time reflecting divergence of systemic and brain temperatures. The x-axis represents the brain-systemic temperature offset, represented respectively for the initial and final time points, both for ipsilateral and contralateral brain temperatures. The rightward shift of all histograms reflects progressive cerebral hyperthermia decoupled from systemic temperatures present for both hemispheres of all 3 subjects.