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The brain functional connectome in post-COVID syndrome

Long COVID syndrome involves a wide range of organ dysfunction and clinical symptoms, but the most frequent, persistent, and disabling symptoms are neurological. In this study, the authors from Germany used resting-state functional magnetic resonance imaging (fMRI) to investigate the characteristics of the brain functional connectome in individuals with primarily neurological symptoms of post-COVID syndrome. 

Despite advances in understanding how infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the brain, the underlying pathological mechanisms of neurological sequelae reported in post-COVID remain hypothetical. Recent in-depth metabolic, microstructural, and functional brain imaging studies have begun to uncover changes in the central nervous system (CNS) related to SARS-CoV-2 infection, which appear macrostructurally unnoticed in conventional brain imaging. These alterations have been found in numerous brain regions across distinct brain networks, such as the olfactory cortex, thalamus, basal ganglia, limbic system, brainstem, and cerebellum.

The authors cited the study of Diéz-Circada et al. who demonstrated substantial network disruptions, manifested as reduced connectivity between the left and right parahippocampal regions and the orbitofrontal and cerebellar areas in 86 individuals eleven months after COVID-19. These changes in the brain network were accompanied by a decrease in the volume of the grey matter in the cortical, limbic, and cerebellar regions and were associated with cognitive dysfunction.

A recent task-activated fMRI study discovered a reorganized working memory network in individuals diagnosed with post-COVID neuropsychiatric symptoms. Several brain regions in the left hemisphere showed lower activation. At the same time, there was a greater or compensatory use of the brain regions in the right hemisphere to maintain normal performance.  These results suggest suboptimal functioning in the normal network, but increased brain activation in the contralateral hemisphere during working memory tasks



About the study

The authors analyzed the resting-state fMRI data in patients with primarily neurological symptoms of post-COVID syndrome. The infection with SARS-CoV-2 was confirmed by reverse transcription polymerase chain reaction of nasopharyngeal swabs for SARS-CoV-2 or the antibodies against SARS-CoV-2 without previous vaccination.

Researchers calculated a set of measures characterizing distinct network features to uncover differences in network topology between patients with post-COVID syndrome and healthy controls. These measures can be distinguished by whether they characterize a feature of the entire graph (global measure) or a feature of individual nodes in the graph (local measure).

All patients with post-COVID symptoms were neurologically examined. Cognitive deficits, affective symptoms, and sleep disturbances were evaluated by using the Fatigue Scale for Motor and Cognitive Functions, the Hospital Anxiety and Depression Scale, the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, the Montreal Cognitive Assessment, and the Trail-Making Test (TMT), parts A and B. The TMT-A is a primarily visual attention skill test, whereas part B is a more complex task and is considered to measure other components of executive functioning.




The study included 123 participants, 66 patients with primarily neurological symptoms of post-COVID syndrome after a mild SARS-CoV-2 infection, and 57 healthy controls. The post-COVID group had a greater proportion of women than healthy controls, 57 versus 38. There was no difference in average age between the two groups, 42.3 years versus 42.1 years. The mean time from the onset of COVID-19 was seven months.


The resting-state fMRI data analysis


There were no significant differences on a whole-brain level for all measures.

However, regional differences were found in the olfactory gyrus, cingulate cortex, red nucleus, thalamus, and crus II of the cerebellum in the post-COVID group.

The functional connectivity was decreased in the olfactory cortex and the medial orbital gyrus which forms the olfactory sulcus and is adjacent to the olfactory tract. The connectivity changes also affected the cingulate cortex, with a decreased connectivity of the anterior cingulate cortex and increased connectivity of the left posterior cingulate gyrus, a central node in the default mode network. Importantly, the findings also revealed the abundance of the angiotensin-converting enzyme 2 receptors, which are important for SARS-CoV-2 viral entry, in the excitatory neurons of the posterior cingulate cortex, interneurons, and cerebellum, potentially rendering these regions vulnerable to acute and long-term damage induced by the SARS-CoV-2 infection.

The TMT-A test, which measures cognitive processing speed, correlated with the connectivity changes in 19 brain regions, such as the cingulate cortex, the insula, and the paracentral lobule. In particular, this test was strongly correlated with the hyperconnectivity of the posterior cingulate gyrus. According to the authors, those findings could contribute to executive function disorders in post-COVID.  For the TMT-B test, which evaluates task-switching capabilities, correlations were found with the connectivity changes in four brain regions.

The red nucleus, a key component of the motor pathway that connects the cerebral cortex to the spinal cord, displayed a significantly decreased connectivity across most regional graphs.

Fatigue, as measured by the total score of the Fatigue Scale, correlated with the connectivity changes in numerous brain regions, with some emphasis on the cerebellum, temporal and occipital lobes, and thalamus. In particular, fatigue was strongly correlated with increased connectivity in the thalamic intralaminar nuclei. These nuclei receive input from various brain regions, including the cortex, basal ganglia, and brainstem, and modulate wakefulness, attention, and sleep-wake cycle.

The Montreal Cognitive Assessment score correlated with the connectivity changes in 12 brain regions, particularly in the cerebellum and bilateral hippocampus. This test strongly correlated with increased connectivity of the right cerebellar crus II, a structure associated with various cognitive functions in working memory and spatial processes.



This study has shown the characteristics and changes of the complex network known as brain functional connectome in individuals diagnosed with post-COVID syndrome. Compared to age- and sex-matched healthy controls, individuals with post-COVID syndrome showed widespread changes in the network architecture of the brainstem, olfactory cortex, cingulate cortex, thalamus, orbitofrontal cortex, and cerebellum.

In addition, the observed changes in the brain’s functional connectome were associated with clinical manifestations, such as fatigue and cognitive dysfunction. The authors suggested that further longitudinal clinical studies should closely monitor the evolution of clinical and imaging findings in post-COVID participants.


This study was published in the Scientific Reports.


Journal Reference

Bungenberg, J., Hohenfeld, C., Costa, A.S. et al. Characteristic functional connectome related to Post-COVID-19 syndrome. Sci Rep 14, 4997 (2024).


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