Many COVID-19 survivors experience symptoms even months after they recover, and while the medical reasoning for this phenomenon continues to elude scientists, a Malaysian neurobiology researcher has proposed a novel hypothesis: The virus could be causing chronic brainstem dysfunction.

Published in ACS Chemical Neuroscience this month, the paper suggests that the virus’ known involvement with the brainstem causes continuous injury to this nearly irreparable organ, perpetuating the typical long-term effects of COVID-19 such as shortness of breath and abdominal pain. These effects are referred to as "long-COVID."

Shin Jie Yong, a neurobiology master's student at Sunway University and the sole author of the paper, explained to The Academic Times that two of the most widely proposed hypotheses for long-COVID point to either residual organ damage or systemic inflammation, an inflammatory response triggered by the immune system. He says that these postulates could be combined under one overarching issue: damage to the brainstem.

To corroborate his theory, Yong conducted a review of relevant literature and examined hundreds of COVID-19 patients' autopsy reports and brain scans. Highlighting that autopsies show that 30% to 40% of deceased COVID-19 patients display the virus’ RNA in their brain, Yong said he also found indications of actual brainstem dysfunction, such as inflammation and neurodegeneration, even in COVID-19 patients with milder forms of the disease.

“If there is damage on the brainstem, such as from direct viral invasion or even systemic inflammation, that sort of encompasses all of the existing hypotheses,” Yong said. “I thought, how can I consolidate what has already been proposed by others?” 

His resulting hypothesis is two-fold.

Yong's research first notes that it is already a proven fact that COVID-19 infiltrates the body by binding to small proteins found on certain cell walls, called angiotensin-converting enzyme 2, or ACE2 receptors. It states that ACE2 receptors are quite abundant on the brainstem, as is neuropilin-1, another entryway for COVID-19. 

In addition to highlighting the brainstem's richness with these important proteins for the virus' pathway, the study calls attention to the organ's preemptive sensitivity to pathological or immune activation, signaled by systemic inflammation as observed in the autopsies.

Aside from the physical signs he found through image review, Yong based his theory on the fact that several functions of the brainstem overlap with many long-COVID symptoms, including respiratory, cardiovascular and gastrointestinal ones. 

Thus, Yong believes the brainstem, crucial for body functions affected by the virus, damaged while enduring COVID-19 and incredibly unlikely to regenerate itself, may be part of a key explanation for the perplexing issue of long-COVID, particularly due to the supporting evidence that his review revealed.

Yong drew attention to another study released very close to his own. Those researchers found that positron emission tomography, or PET, scans of COVID-19 patients demonstrated hypometabolism in the organ, a frequent factor in many neurodegenerative diseases, as compared with healthy controls.

This provides more tangible proof of brainstem dysfunction in COVID-19 patients, and even adds onto it, Yong argues, by examining portions of the brain beyond the brainstem as well. However, Yong emphasized that there are likely more pieces to the puzzle.

“It would confirm it in such a way that the brainstem hypothesis actually explains long-COVID, but there might be other causes,” he said. “The new study discovered that there is hypometabolism at the brainstem, but in the future, there might be other molecular explanations.”

The term long-COVID was first used as a Twitter hashtag by Elisa Perego, a patient from Lombardy, Italy, in trying to summarize her post-virus experience. Like Perego, victims of long-COVID experience loss of smell, difficulty breathing, excessive fatigue or other symptoms similar to those they underwent while infected by the virus, but up to six months after they recover. For instance, over 30% of survivors report experiencing shortness of breath or chest pain for about two to three months after recovery, the paper explains.

Yet, the scientific community originally dubbed the condition a psychological concern.

“Initially, long-COVID wasn't recognized as a medical problem. Doctors just dismissed the concept as problems related to mental health,” Yong remarked. “Later on, long-COVID sufferers around the world formed social support groups and finally, the scientific community started to pay attention.”

Yong stressed that the main force behind his research into this topic is that scientists need to quickly provide a true medical reason for long-COVID, in order to adjust its status as purely a mental health concern. 

“If the brainstem hypothesis is true, then that will provide a legitimate medical phenomenon behind long-COVID," he said, “which would further substantiate long-COVID as a medical problem.”

The paper, "Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis," published Feb. 4 in ACS Chemical Neuroscience, was authored by Shin Jie Yong, Sunway University.