The aim of this study, conducted by the US research group, was to investigate whether participants with a post-COVID condition and neuropsychiatric symptoms had abnormal brain activation during a working memory task. The authors also examined the possible relationship between abnormal brain activation and performance on three NIH-Toolbox (NIHTB) batteries of cognitive, emotional, and motor functions.
More than two years after the global COVID-19 pandemic, it is clear that infection with severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) can lead to a new disease called post-acute COVID syndrome or long COVID. Patients with long COVID have a wide range of organ dysfunction and clinical symptoms. The most common, persistent, and disabling symptoms of long COVID are neurologic, and result in long-term functional impairment.
While studies have comprehensively mapped the spectrum of neurologic sequelae in patients with long COVID, there has been no significant progress in understanding the underlying mechanisms. Because SARS-CoV-2 causes various neurologic sequelae, several mechanisms could be involved, and thus, several theories have been proposed. Direct neuroinvasiveness and neurotropism of SARS-CoV-2 have been demonstrated in experiments with animals and CNS organoids, with deleterious effects on infected and neighboring neurons. However, there is evidence of direct primary infection of brain cells with SARS-CoV-2. Post-mortem examinations of the brains of COVID-19-positive patients revealed that viral RNA levels were very low or undetectable, and did not correlate with significant histopathologic changes, such as hypoxic/ischemic changes, hemorrhagic infarcts, and microglial activation with microglial nodules, particularly in the brainstem and periventricular subcortical white matter. https://discovermednews.com/why-does-long-covid-look-like-a-neurological-disease/Â
About the study
The authors used blood-oxygenation-dependent functional MRI (BOLD-fMRI) to examine brain activation in 50 participants (29 post-COVID and 21 controls) during a working memory task. Participants with a post-COVID condition had documented COVID-19 at least 6 weeks before enrollment. Healthy controls had no history of COVID-19 and tested negative for SARS-CoV-2. Of the 50 usable fMRI datasets, nine participants (six post-COVID, three controls) had minor abnormalities on their structural MRIs that were not exclusionary. Five (3 post-COVID participants, 2 controls) had slightly more than age-related white matter lesions, two (one in each group) had lacunar infarcts, one control had microhemorrhages, and one control had both a small old infarct and a microhemorrhage.
Participants were assessed with three NIHTB batteries for cognition (NIHTB-CB), emotion (NIHTB-EB) and motor function (NIHTB-MB), and with selected Patient-Reported Outcomes Measurement Information System (PROMIS) tests.
Post-COVID-19 participants reported a high prevalence of cognitive disorders, such as concentration problems (93%), memory problems (79%) and confusion (64%). They also reported neurological symptoms, headaches (57%), visual disturbances (50%), gait disturbances (50%), paresthesias (43%), and coordination problems (39%).
In addition, they had a high prevalence of new other symptoms, including fatigue (86%), depression/anxiety (68%), sleep disturbances (64%), myalgia (61%), light-headedness (46%), and urinary problems (28%).
Results showed no group differences in brain activation during the 0-back and 1-back tasks between post-COVID-19 participants and healthy controls. However, in the more difficult 2-back task, results showed that brain activity in the post-COVID participants differed from activity recorded in healthy control participants without a history of COVID-19. Results suggest suboptimal functioning in the normal network, but increased brain activation in the contralateral hemisphere during working memory tasks.
In the 2-back task at the uncorrected cluster-level, several brain regions showed lower activation in post-COVID participants than in controls. The two large clusters with lower activation included regions in the left hemisphere- postcentral gyrus, insula, precentral gyrus, and inferior parietal lobule regions. However, all brain regions with higher activation in the 2-back task in the post-COVID group than in the control group were in the right hemisphere. The post-COVID group had lesser deactivation in the right posterior cingulate and greater activation in the right superior frontal gyrus. Despite these group differences in brain activation, the two groups had similar accuracy and reaction time for each task. In addition, the post-COVID participants reported a high prevalence of memory (79%) and concentration (93%) complaints, but showed normal performance in all seven cognitive domains of the NIHTÂ battery for cognition.
In the NIHTB battery for motor function, the post-COVID-19 participants performed worse than healthy controls in the domains of endurance, locomotion and the manual dexterity of the dominant hand (controlled by the motor area of the dominant hemisphere).
In emotional NIHTB battery, the post-COVID participants showed significantly worse psychological well-being than controls.
The role of plasticity in recovery from brain damage
The results of this study suggest a reorganized working memory network, with greater or compensatory use of the brain regions in the right hemisphere to maintain normal performance. At the same time, on the NIHTB battery for motor function, the post-COVID-19 participants performed worse than the control group for endurance, locomotion and dexterity of the dominant hand.
Brain plasticity is greatest during the developmental period, but the capacity for substantial plasticity persists into adulthood. Disease-induced cortical reorganization is be best thought of as a process involving early functional changes followed by structural changes that consolidate functional reorganization. Structural changes provide a substrate for substantial plasticity. Functional changes typically include changes in synaptic strength, possibly due to long-term potentiation or long-term depression.
Following a brain lesion, changes in other brain regions have been documented at different time points after the lesion, ranging from minutes to months. Postlesional events may be due to deafferentation, removal of inhibition, activity-dependent synaptic changes, changes in membrane excitability, growth of new connections, or unmasking of preexisting connections. Following damage to the nervous system, large-scale rewiring has been described.
In particular, recovery after stroke involves functional changes characterized by increased activity of the motor cortex in the contralateral hemisphere. This process represents a kind of adaptation using available resources. There is considerable debate about the persistent reorganization in the contralateral hemisphere. It is thought that persistent activation in the unaffected contralateral hemisphere after injury to the primary motor cortex correlates with poor recovery and represents maladaptive plasticity. In contrast, the other authors suggest that increased activity in the contralesional hemisphere may contribute to functional improvement, particularly in less-well recovered patients. These results suggest that the same approach may not be appropriate for all patients.
Conclusion
This is the first task-activated BOLD-fMRI study in the post-COVID participants with neuropsychiatric symptoms. The results show that brain activity in the post-COVID participants differs from that of healthy control participants with no history of COVID-19.
Several brain regions that showed lower activation in post-COVID participants than in controls included regions in the left hemisphere. At the same time, the post-COVID-19 participants performed worse than controls on the NIHTB battery for motor function, in endurance, locomotion and the dexterity of the dominant hand. In contrast, all brain regions that were more activated in 2-back task in the post-COVID group than in the control group were located in the right hemisphere.
These results suggest suboptimal functioning in the normal network, but increased brain activation in the contralateral hemisphere during working memory tasks. The authors concluded that BOLD-fMRI was sensitive to detect a process of brain reorganization in the post-COVID participants with neuropsychiatric symptoms.
This article was published in the Neurology. Chang L. Et al. Changes in Brain Activation Pattern During Working Memory Tasks in People With Post-COVID Condition and Persistent Neuropsychiatric Symptoms. Neurology, April 26, 2023 (Open Access). https://n.neurology.org/content/early/2023/04/26/WNL.0000000000207309