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

Discussion

These findings represent, to our knowledge, the first such demonstration of dynamic ischemic brain temperature monitoring by using fully noninvasive MR thermometry. With a controlled NHP stroke-induction model, the findings confirmed: 1) the presence of physiologic brain temperature gradients in the healthy brain, 2) disturbance of brain temperatures following ischemia, and 3) decoupling of baseline brain systemic temperature gradients as hypothesized, in a phylogenetically similar substrate offering potential insight into human spatiotemporal brain temperature disturbance.

Febrile systemic temperatures are a well-known consequence of large-vessel-occlusion stroke, particularly in the later acute phase of ischemia; however, the immediacy with which brain temperatures increased in our study suggests that damaging brain temperature elevations may indeed begin early following infarction. Cerebral temperatures correlated strongly with infarction volumes in this study, and while a causal relationship could not be established in our experimental design, the findings are consistent with existing reports of infarction expansion and poor outcome among fully revascularized patients with febrile stroke.^{8,10,11,13,26,38,39} Brain temperature regulation is expected during systemic febrile responses; however, these findings support the notion that brain injury may attenuate inherent brain thermoregulatory mechanisms.^{7,11,18,37,40} More surprising perhaps is the rapid decoupling of brain systemic temperatures as observed in this study, whereby brain temperatures steadily outpaced even the increasing systemic temperatures. Several potential explanations can be considered, which at present remain difficult to conclusively establish: First, cerebral temperatures may theoretically surpass systemic temperatures in hypoperfused-but-viable tissues (ie, the putative ischemic penumbra), where metabolically active but ischemic tissues are perfused insufficiently to ensure ready clearance of metabolic heat.^7,37,41,42 This, by comparison to more mature areas of infarction among which hypoperfusion of metabolically inert tissues may be inconsequential with respect to temperature in the acute phase before inflammatory cascades initiate. This explanation seems unlikely, at least in isolation, given that such changes would be expected locally or regionally, rather than globally affecting both hemispheres as observed in our study. The relation among temperature, viability, and perfusion could not be tested rigorously in this study, as discussed further among the limitations below, but nevertheless the impact is likely only partial.

A second consideration may be that of heating influences on cerebral tissues related to inflammatory pathways at play following infarction. Recent investigations have emphasized the immunologic basis of stroke progression, underscoring numerous effectors of stroke progression.^43,44 Importantly, these temperature changes occur independent of infection and appear to be driven by pyrogenic cytokines or lymphocyte trafficking.⁹ These increasing temperatures may, in turn, beget further injury, driving progression of infarction and degrading the temperature-sensitive blood-brain barrier, inciting a continued cycle of injury. Whether immunologic mechanisms can be imputed in these findings remains to be studied but could represent a treatment target, perhaps allowing neuroprotection, together with therapeutic hypothermia, as proposed in other settings. Last, tissue swelling developing with ischemia could compete with heat dissipation to the brain surface; however, heat conduction is primarily believed to modulate surface brain temperatures and is therefore likely a less important variable in comparison with hemodynamic, metabolic, or immunologic factors.^5,21,22,24

While simulations and biophysical models of brain temperature regulation have been proposed, validation by direct in vivo observations is limited to a relatively small number of human and nonhuman animal studies.^{2,3,5,17,21,24,26,28,45⇓⇓–48} Prevailing paradigms highlight the complexity of brain temperature as a biomarker, reflecting the intersection of complex metabolic and hemodynamic pathways.^5,22 Accordingly, brain temperature may, to some extent, be viewed as an epiphenomenon to heat-producing metabolic pathways (primarily the cleavage/use of oxygen delivered by the heme moiety within circulating red blood cells) and heat-dissipating mechanisms (consisting principally of circulating blood flow) critical to elimination of thermal waste through countercurrent heat-sink mechanisms, which depend on brain systemic temperature gradients.^1,3,17,49 Thus, temperature may be an indirect product of brain metabolic homeostasis, albeit directly affected by hypothalamic or other controls, including proximity to the brain surface, CSF spaces, and pneumatized cells of the paranasal sinuses. The development of refined systems to protect the brain from dangerous heating, such as during systemic hyperthermia, may have paralleled loss of the rete caroticum in humans and NHPs.^1,3,17,49 Critically, however, the injured brain may lose this thermoregulatory capacity, allowing brain heating under systemic or even local-regional influences.

Practical considerations have historically challenged the study of brain temperature regulation and the development of a generalizable formalism, due to the absence of safe, direct brain thermometry techniques.^{3,17,26,45,46,50} Generally limited to invasive and costly implantable probes and thermocouples, the spatial distribution of temperature has remained relatively unaddressed. Past studies have suggested that brain temperature, at least centrally, exceeds systemic temperatures due to its high metabolic rate, consuming 20% of oxygen and 25% of glucose at rest, yet accounting for only 2%–3% of body weight.^5,9,24,48 The use of noninvasive, temperature-sensitive nuclear magnetic resonance phenomena has been proposed for this purpose, and a variety of potential methodologies exist within the current armamentarium.^{28,33,34,42,51} MRSI proves particularly advantageous because identification of an internally referenced chemical shift difference such as that between brain-water and N-acetylaspartate permits nearly absolute thermometry, critical for thermograph production across imaging sessions and facilitating intra- and intersubject temperature characterization, by comparison with faster but purely relative phase-contrast thermometry.^33,34 A previous phantom-optimization study tested 3 distinct analysis methods, all of which performed extremely well compared with real-time fiber-optic temperature monitoring (R² > 99, root-mean-square deviation ∼ 0.005, P < .001), and we proposed an extension of this approach for multiphasic, multivoxel NHP brain thermometry in the current study. The findings in the present study differ in important ways from those in past investigations, including recent reports by Karaszewski et al⁷ of noninvasive brain thermometry following acute ischemic stroke in humans. Specifically in their study, initial MR imaging may have been delayed by >24 hours from the time of onset and not repeated until 3–7 days following presentation. Similarly, baseline temperatures before stroke onset critically inform the magnitude and direction of temperature disturbance but cannot be reasonably obtained outside the setting of controlled stroke induction.

The Rhesus Macaque brain provides a robust prehuman experimental model in stroke neuroscience, in which rodent and lower primate protocols may fail translation to humans.⁵² MRSI in the Rhesus brain, however, poses certain challenges. The exuberant cranial fat may significantly degrade spectral quality, despite meticulous outer volume suppression or fat-water separation strategies. To address these limitations, an optimized approach combines sLASER spectroscopy with improved shimming routines (gradient refocused echo shim) to better offset commonly suboptimal shim conditions near the brain surface.^31,53 In doing so, superior MR spectroscopy thermometry can be achieved, with higher spectral quality, greater SNR, longer metabolite T2*, and amelioration of chemical shift displacement artifacts corrupting conventional approaches to MRSI.

We acknowledge several study limitations, including primarily the sample size. We sought to characterize brain temperatures under physiologic and controlled ischemic conditions, with sufficiently high temporal sampling, to inform a basic paradigm of spatiotemporal temperature evolution and brain-systemic temperature coupling. Experimental demands of sourcing NHPs to conduct 12–15 hours of MR imaging during 7–10 days of animal care and to undertake stroke induction prohibited greater recruitment. Nevertheless, recent expert consensus has emphasized the importance of stroke neuroscience research models in gyrencephalic primates to bolster translational research designs and facilitate applicability to human physiology and disease.^52,54 The invasive study of NHPs more importantly presents ethical considerations demanding thoughtful study design, and to this end, the present study was guided by contemporary philosophies on the humane treatment of study subjects to eliminate or minimize pain, distress, anxiety, and depression.⁵²

Similar considerations precluded the addition of a control population of nonischemic or sham-operated NHPs, and potential bias in this respect cannot be excluded. The experimental design furthermore limited our ability to acquire reliable, contemporaneous perfusion data in study subjects. Certainly, cerebral perfusion would represent a valuable adjunctive parameter in this setting; however, hardware limitations precluded acquisition of arterial spin-labeling perfusion by using the same transmit-receive coil system tuned and configured for optimized NHP brain imaging and spectroscopy. A 2-coil arterial spin-labeling solution was not achievable with our experimental resources, and multiphasic dynamic susceptibility contrast perfusion could not be performed due to unrecoverable degradation of proton resonance spectra for accurate thermometry. Further study of the relation among perfusion, temperature, and viability, ideally coupled to oxygen metabolism, are warranted and the subject of investigation in our laboratory.

Despite the absence of perfusion imaging, the present study offers valuable insight into cerebral thermoregulation and dysregulation in a biologically relevant model of acute ischemic stroke. The use of the chemical shift difference between brain-water and N-acetylaspartate could theoretically be impacted by diminishing NAA concentrations in injured tissues, precluding identification of resonance signatures and therefore thermometry; however, in agreement with earlier studies by Corbett et al,²⁷ NAA concentrations throughout the early aftermath of stroke remained sufficient to permit thermometry, though a more extended survival study beyond the acute stage could potentially require the use of another non-hydrogen-bound proton metabolite as previously described.

Last, the impact of anesthesia induction must be addressed. General anesthesia may significantly affect brain or body temperatures; however, this pharmacologic profile played favorably into our design, in which all 3 baseline scans, stroke sessions, and poststroke day scans shared a common induction protocol. This feature proved valuable as an additional form of physiologic contrast, allowing, first, for characterization of brain systemic gradients during the initial cooling phase following induction, at which time the subject was exposed to cool ambient temperatures. Thereafter, during systemic warming by the circulating water blanket, brain and systemic (rectal) temperatures could be monitored simultaneously. Cooling maneuvers were not prescribed in our protocol, and when subject temperatures began to exceed physiologic temperatures set by the water bath, as they invariably did under the heating blanket, the water bath automatically powered down and the blanket was removed.

Significant systemic temperature elevations were not specifically noted among the 3 examination sessions, perhaps due to the very early postinfarction monitoring period, in comparison with the slightly more delayed fevers described in recent stroke studies. However, of interest to our understanding of these mechanisms is that the cerebral-systemic gradient changed only minimally during physiologic baseline scanning, despite clear changes to each independently, following anesthesia induction and subsequent rewarming. In contrast, progressive uncoupling of brain and systemic temperatures was consistently observed after stroke, despite escalations in both, consistent with existing hypotheses that brain injury impairs cerebral thermoregulation independent of systemic temperatures. The strongest evidence for such decoupling may come from poststroke (t¹) scans, in which even early postanesthesia thermographs during diminished systemic temperatures revealed elevated brain systemic gradients before systemic rewarming by the heating blanket could be achieved as shown in Table 1. This finding may suggest that therapeutic targets for brain cooling may be necessary, even in advance of the development of systemic febrile responses, often delayed for days following stroke.