- Breathlessness, chronic fatigue, and other long-COVID symptoms may slowly improve. However, brain fog may worsen with time.
- Although brain fog in long COVID may look like ADHD, Mild Cognitive Disorder, or other neurological disorders, the underlying mechanisms differ.
- An ADHD medication, Guanfacine, and antioxidant, NAC, were used on a small sample to treat long-COVID brain fog.
- Future treatments should target brain inflammation to address the currently known causes of long-COVID cognitive deficits.
Sufferers of long COVID experience symptoms that may persist for weeks, months, or even years after contracting the COVID virus. Some researchers and clinicians have listed as many as 200 long COVID symptoms. The most frequently reported symptoms are breathlessness, chronic fatigue, and brain fog. The breathlessness, chronic fatigue, and other symptoms may slowly improve; however, brain fog may worsen with time.
Brain fog is a foggy term. It is not specific, which makes it challenging to study. Another way of describing the commonly reported cognitive issues is cognitive impairment or deficits. I also don't believe that conceptualizing the post-COVID brain changes as impairments, deficits, or dementias is accurate. Post-COVID cognitive changes may look like other neurological disorders, such as dementia, ADHD, or traumatic brain injury. But it is important to keep in mind that the underlying biological mechanisms may not be identical. This is an important consideration for treatment.
Many people who suffer from neuro-long COVID indeed perform like those with mild cognitive impairment on neuropsychological assessments. This is certainly concerning enough for researchers to find mechanisms and treatments based on this understanding.
These long-COVID symptoms can look like attention deficit disorder (ADHD). The hallmark symptoms of ADHD are difficulty focusing, short attention span, difficulty multitasking, and executive dysfunction. One can use the vague term "brain fog" to also describe a person's experience with ADHD. Pathologies in the brain's dopamine and norepinephrine systems have been proposed as the underlying mechanisms of ADHD. Hence, the management of ADHD symptoms has focused on amplifying the dopamine and norepinephrine brain signals.
A new study
To connect all these observations, a study on a very small sample size tested a currently used ADHD medication for long COVID (N=12).1 Guanfacine was approved for the treatment of ADHD in 2009. It was developed in the lab of Amy Arnsten, one of the authors of this report. The medication is combined with N-acetylcysteine (NAC-600 mg), an antioxidant for treating Traumatic Brain Injury (TBI). Eight out of the 12 patients studied reported improvements in memory, organizational skills, and ability to multitask. No objective tests were used to verify the patients' reported improvements. Two patients were unavailable for follow-up; the other two discontinued the medication due to intolerable side effects, such as low blood pressure and dry mouth.
This is not a placebo-controlled study and is considered anecdotal. Double-blind and placebo-control studies with much larger samples should be conducted before prescribing ADHD medications to long COVID sufferers. Also, one of the report's authors receives royalties from the U.S. sales of Intuniv (extended-release guanfacine).
As explained earlier, the proposed mechanism of ADHD cognitive symptoms (attention, focus, and memory) is dopaminergic/adrenergic pathologies. We have begun to understand the underlying mechanisms of long COVID. A recent paper proposed six underlying mechanisms of long-COVID cognitive changes2:
1. Immune system's response to the virus increases molecules such as cytokines and chemokines, which can put the brain on fire (neuroinflammation).
2. The virus itself can directly infect the brain.
3. The virus can give rise to an autoimmune response where the brain attacks its own cells.
4. The virus can wake up dormant herpesviruses, like the Epstein-Barr virus, damaging the brain and leading to cognitive impairments.
5. The virus and the resulting biological response can impair blood circulation, which provides the conduit of nourishments to brain cells.
6. Multi-organ dysfunctions in severe COVID cases can cause hypoxemia (a below-normal level of oxygen in your blood, specifically in the arteries) and metabolic disturbances that deprive brain cells of oxygen and nourishment and, in turn, provoke cell death.
Where can we go from here?
It would be more beneficial to target the currently known mechanisms of brain changes in long COVID to search for efficient and effective treatments. Specifying the exact brain changes in long COVID using sensitive neuropsychological tests is crucial. The symptoms reported by long COVID patients, such as memory problems, might result from dysfunctions in other faculties, such as attention, default mode network, processing speed, neuroplasticity, neuro-inflammation, etc. Also, following the trajectory of these cognitive symptoms is essential. Cognitive deficits do not always lead to dementia or permanent decline.
As a sufferer of long COVID since 2020, the problem with my long-COVID brain is not one of memory deficit. It is more like the time scale used by the brain is much slower than the actual time. By the time the next moment begins, I am still processing the previous one. Or I stop processing the previous one in favor of hoping to catch the next one fully.
Also, the long-COVID brain struggles with multitasking, tasks requiring a long attention span, and intense focus. The byproduct of this slowing of brain machinery is memory deficits. While using strategies to improve memory would help, addressing the more direct mechanism would be better.
(1) Fesharaki-Zadeh, A., Lowe, N., & Arnsten, A. F. (2023). Clinical experience with the α2A-adrenoceptor agonist, guanfacine, and N-acetylcysteine for the treatment of cognitive deficits in "Long-COVID19". Neuroimmunology Reports, 3, 100154. https://doi.org/10.1016/j.nerep.2022.100154
(2) Monje, M & Iwasaki, A. (2022). The neurobiology of long COVID. Neuron, 110, 3484-3496.