Whole-brain MRI maps a key brain energy reaction

The brain has exceptionally high energy demands. Even at rest, it requires a continuous supply of ATP, and during neural activity this demand can increase rapidly. Because neurons have limited capacity to store energy, the brain depends on fast biochemical reactions that stabilize ATP availability on short timescales. Many of these reactions, however, remain difficult to measure directly in vivo, particularly across the whole brain.

A central component of this energy buffering system is creatine kinase (CK). CK catalyzes the reversible transfer of a phosphate group between phosphocreatine and ATP, allowing cells to rapidly regenerate ATP when demand increases. Through this mechanism, CK plays a key role in maintaining energy homeostasis during changes in neuronal activity.

CK is not merely a constitutive “housekeeping” enzyme. Alterations in CK turnover and kinetics have been associated with aging, neurodegenerative disease, psychiatric disorders, and cancer. Despite its importance, noninvasive measurement of CK activity in the human brain has remained challenging. Phosphorus-based magnetic resonance techniques can probe CK reaction rates, but they typically suffer from limited sensitivity and require long acquisition times or provide only restricted spatial coverage.

Creatine kinase imaging

A team led by Lijing Xin at EPFL’s Metabolic Magnetic Resonance Spectroscopy Group (CIBM Center for Biomedical Imaging) has now developed creatine kinase imaging (CKI). The technique produces three-dimensional, whole-brain maps that measure how quickly brain cells can regenerate ATP when energy demand rises in vivo.

The method, published in PNAS, was implemented and validated on a clinically approved 7 Tesla MRI scanner. The researchers also developed a functional version, functional CKI (fCKI), designed to detect changes in CK activity during brain activation.

How CKI works

CKI builds on magnetic resonance fingerprinting, a strategy that estimates several parameters from one carefully designed measurement. Rather than running many separate scans, the sequence applies a defined pattern of radiofrequency pulses and timing changes. Each voxel produces a characteristic signal evolution that can be matched to a model of the underlying physics and chemistry.

Here, the chemistry of interest involves phosphorus-containing metabolites central to energy metabolism, especially phosphocreatine and ATP. CKI targets these signals and fits them to a chemical exchange model to estimate the measure of how quickly brain cells can regenerate ATP when energy demand rises.

In the same workflow, CKI can also map the phosphocreatine/ATP concentration ratio, how quickly the phosphocreatine signal settles back after a radiofrequency pulse, and small shifts in the scanner’s magnetic field across the brain (used to correct the maps).

The researchers built the method as a largely automated, push-button acquisition and reconstruction pipeline. The initial whole-brain demonstration used a scan time of about 49 minutes, but further analysis suggested that using half the data could enable a shorter protocol of about 25 minutes while maintaining consistent estimates across most brain regions.

Testing CKI and fCKI on volunteers

In healthy volunteers, CKI produced whole-brain maps that revealed regional differences in CK reaction rates. Among the regions analyzed, the parietal lobe showed the highest this ATP-regeneration speed values, while the putamen showed the lowest.

The occipital lobe also showed high this ATP-regeneration speed values. When averaged across the whole brain, the study did not find a significant overall difference in this ATP-regeneration speed between gray matter and white matter, even though other parameters, such as PCr/ATP, differed between these tissue types.

The team then used fCKI during a visual stimulation paradigm that alternated rest and flashing checkerboards. In each participant, CK activity increased in the visual cortex. In the occipital lobe, the mean relative increase in this ATP-regeneration speed was 13.7%, and voxel-wise analysis highlighted localized activation clusters with larger increases in the posterior brain.

Implications and applications

CKI and fCKI offer a way to view brain function through a bioenergetics lens. Instead of only showing where energy-related metabolites are, the approach estimates how fast a key energy-buffering reaction runs, and how it changes with activity.

The findings suggest that whole-brain mapping of CK kinetics may be useful for research into neurological and psychiatric disorders where brain energetics are altered, and for exploring strategies that target creatine and CK-related energetics.

Other contributors

• University of Michigan
• Shantou University Medical College