by Xiaopeng Song

If you go to the gym frequently, you might have heard about creatine. Taking creatine as a supplement is very popular among athletes and bodybuilders. It helps their muscles produce energy during intense workouts and therefore improves exercise performance. The magic behind this practice is that the high-energy phosphate moiety of adenosine triphosphate (ATP) can be rapidly transferred to creatine to generate phosphocreatine (PCr) in a reversible reaction catalyzed by the enzyme creatine kinase (CK), and the PCr is used to regenerate ATP when the demand for energy is high. Thus, PCr acts as an energy reservoir and maintains relative stable ATP levels during exercises. But did you know that the CK reaction is also important for brain functions, and that a decreased CK reaction rate is associated with abnormal brain activities in psychotic patients? Our recent study demonstrated these findings.

Like our muscles, our brains consume a lot of energy every day—approximately 20 watts to maintain spontaneous neuronal activity. Our daily cognitive tasks are performed not only by discrete brain regions, but also by brain networks. When these anatomically remote brain regions work together as a network, they need to coordinate with each other by synchronizing their neural activities, or in other words building up “functional connectivity”. Impaired functional connectivity is associated with declined cognition, impaired memory, or even psychosis. While it may seem intuitive that coordinated neural activities or functional connectivity are energy consuming, there was no in vivo human study directly and quantitatively linking functional connectivity to energy metabolism prior to our work.

Using advanced brain imaging techniques, we quantified the regional energy generation rate catalyzed by the CK reaction and brain functional connectivity in both healthy subjects and patients with schizophrenia or bipolar disorders. We found that both measures were decreased in psychotic patients, and a higher energy generation rate was correlated with the stronger brain functional connectivity in healthy controls. However, this correlation was compromised in patients. These findings indicate that lower energy generation rates might disrupt the long distance and large-scale neuronal communications—thereby leading to brain disorders. Our study revealed the general principle of brain energy-activity organization and suggests that the metabolism-neural synchrony pathway could be a new potential treatment target for psychotic disorders.

The highlighted cortical regions above are the nodes of a large-scale brain network. These areas usually show synchronized neural activity or in other words, functional connectivity (FC), as they work towards a common goal. In this study, a positive correlation was found between the strength of this synchronization or connectivity and the rate of the creatine kinase reaction, which would be critical for orchestrating oscillatory states, and enhancing the fidelity of information processing for better executive and cognitive function.

Xiaopeng Song is a postdoctoral fellow in the lab of Dr. Fei Du at McLean Hospital, Harvard Medical School.

Learn more in the original research article:
Bioenergetics and abnormal functional connectivity in psychotic disorders.
Song X, Chen X, Yuksel C, Yuan J, Pizzagalli DA, Forester B, Öngür D, Du F. Mol Psychiatry. 2021 Jan 4. doi: 10.1038/s41380-020-00993-z.