Abnormal brain diffusivity in participants with persistent neuropsychiatric symptoms after COVID-19, 2023, Liang et al.

[SNT Gatchaman]

Abnormal brain diffusivity in participants with persistent neuropsychiatric symptoms after COVID-19
Huajun Liang; Thomas Ernst; Kenichi Oishi; Meghann C. Ryan; Edward Herskovits; Eric Cunningham; Eleanor Wilson; Shyamasundaran Kottilil; Linda Chang

Objectives
We aimed to compare brain white matter integrity in participants with post-COVID-19 conditions (PCC) and healthy controls.

Methods
We compared cognitive performance (NIH Toolbox ® ), psychiatric symptoms and diffusion tensor imaging (DTI) metrics between 23 PCC participants and 24 controls. Fractional anisotropy (FA), axial (AD), radial (RD), and mean (MD) diffusivities were measured in 9 white matter tracts and 6 subcortical regions using MRICloud.

Results
Compared to controls, PCC had similar cognitive performance, but greater psychiatric symptoms and perceived stress, as well as higher FA and lower diffusivities in multiple white matter tracts (ANCOVA-p-values≤0.001–0.048). Amongst women, PCC had higher left amygdala-MD than controls (sex-by-PCC p=0.006). Regardless of COVID-19 history, higher sagittal strata-FA predicted greater fatigue (r=0.48-0.52, p<0.001) in all participants, and higher left amygdala-MD predicted greater fatigue (r=0.61, p<0.001) and anxiety (r=0.69, p<0.001) in women, and higher perceived stress (r=0.45, p=0.002) for all participants.

Conclusions
Microstructural abnormalities are evident in PCC participants averaged six months after COVID-19. The restricted diffusivity (with reduced MD) and higher FA suggest enhanced myelination or increased magnetic susceptibility from iron deposition, as seen in stress conditions. The higher amygdala-MD in female PCC suggests persistent neuroinflammation, which might contribute to their fatigue, anxiety, and perceived stress.

Link | PDF (NeuroImmune Pharmacology and Therapeutics)

 

[SNT Gatchaman]

Neuroinflammation can be non-invasively evaluated in humans using diffusion tensor imaging (DTI). DTI has been widely used to detect brain microstructural abnormalities caused by various neuropathology, including neuroinflammation. DTI evaluates tissue microstructure by measuring the movement of water molecules. Persistent neuroinflammation can cause fiber demyelination, degeneration, and neuronal damage; consequently, water movement becomes more diffuse, corresponding to higher diffusivity indices. DTI studies that evaluated brain abnormalities in COVID-19 found both higher and lower white matter diffusivity within six months of acute infection.

Conversely, lower diffusivities were also reported in participants who had a high prevalence of neuropsychiatric symptoms during acute infection (68.3%) and 3 months later (55%). However, no DTI study has specifically evaluated only participants with PCC.

We hypothesized that (1) recovered COVID-19 participants with PCC would have ongoing neuroinflammation, which would be shown by higher diffusivity and lower fractional anisotropy (FA) in the cerebral white matter compared to those in the controls, and (2) the higher diffusivity and lower FA in the selected regions of interest would predict both poorer emotional health and cognitive performance.

 

[SNT Gatchaman]

Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) values were obtained for 9 major white matter fiber tracts (corpus callosum, corona radiata, internal capsule, external capsule, cingulum, sagittal stratum, fronto-occipital fasciculus, longitudinal fasciculus, uncinate fasciculus) and MD for 6 subcortical grey matter regions (amygdala, hippocampus, caudate nucleus, putamen, globus pallidus, thalamus).

 

[SNT Gatchaman]

Our finding of white matter restricted diffusivity with lower MD and higher FA in PCC relative to control groups is consistent with a prior DTI study but opposite from our initial expectation of neuroinflammation-induced elevated white matter MD.

Our finding is consistent with two recent studies that examined the CSF of nearly 150 patients with PCC, which found that none of the CSF samples contained SARSCoV-2 RNA, intrathecal SARS-CoV-2 antibodies, or inflammatory markers, suggesting no on-going neuroinflammation in PCC patients.

In our PCC participants, the lower than normal MD reflects restricted diffusivity in the white matter tracts and indicates more hindrance of water movement (intraaxonal, extra-axonal, or extra-cellular compartments); the higher than normal FA values represent more coherent or compact fibers. Several physical or pathological processes in the brain that can lead to lower diffusivity and higher FA include enhanced myelination, increased magnetic susceptibilities, and cytotoxic edema.

Enhanced myelination, such as that seen during normal neurodevelopment or a repair process in our PCC participants, would lead to more compact fibers, increasing water movement parallel to the axons while reducing water movements perpendicular to the fibers.

Another condition that can lead to enhanced myelination and fiber reorganization, represented restricted diffusion and elevated FA, is chronic stress. First, stress activates neurons and the release of glucocorticoids, which can trigger oligodendrogenesis to enhance myelination. Patients with post-traumatic stress disorder (PTSD) for 7 years showed higher myelin content, assessed via myelin water imaging

 

[SNT Gatchaman]

Compared to the controls, recovered COVID participants with persistent neuropsychiatric symptoms had higher FA and restricted diffusivity in several white matter regions and higher mean diffusivity in the left amygdala. These microstructural abnormalities in the white matter were contrary to what we initially hypothesized. These findings may reflect enhanced myelination resulting from stress, increased magnetic susceptibility from iron dysmetabolism, or less likely, ongoing cytotoxic edema. Importantly, our findings demonstrate that brain abnormalities persist for an average of six months or longer in patients with long COVID symptoms.

See threads tagged with myelin and in particular —

Myelin lipid metabolism and its role in myelination and myelin maintenance (2022)

These findings may relate to the observations of increased brainstem volume and white matter variation in —

Brainstem volume changes in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID patients (2023)
Anti-Correlated Myelin-Sensitive MRI Levels in Humans Consistent with a Subcortical to Sensorimotor Regulatory Process (2022)

 

[rvallee]

Compared to controls, PCC had similar cognitive performance

Then you tested it wrong. Cognitive impairment is one of the most reported issues, and one of the most disabling. This is not credible.

And clearly, badly want to attribute this to "stress", which is always poorly assessed and without any depth. I don't even understand what chronic stress as a condition could mean. It's a factor, not a condition in itself, and being disabled without support is always stressful, especially if it's defined through the most common symptoms of illness.

It's frankly looking more and more as if the obsessive need to prove psychogenic stuff is taking up most of the motivation overall. Trying very hard to show a specific direction of causality, and only the one.

This isn't good science, it is too biased. Even when they find things, they scramble to attribute them to the traditional stuff. Instead of solving problems, they're trying to reassess past failures and give them all new excuses, that happen to be the exact same old.

 

[SNT Gatchaman]

Yes I did wonder whether I should write a caveat to ignore the suggested mechanisms, esp with regard to stress. The classification of all these symptoms as neuropsychiatric is of course unevidenced.

PCC participants were required to have a documented history of COVID-19 at least 6 weeks earlier and had at least one new cognitive or neuropsychiatric symptom after COVID-19 (i.e., memory complaints, headache, “brain fog”, loss of taste or smell, fatigue, depression or anxiety, sleep disturbances, pain).

I don't know why the included criteria included memory complaints, brain fog and yet the results showed —

PCC participants and controls had similar performance on all cognitive assessments. However, the PCC group had higher levels of depression (p=0.001), anxiety (p=0.001), fatigue (p<0.001), Pain-Interference (p<0.001), perceived stress (p=0.001), and poorer global mental health (p<0.001) compared to those in the controls.

Anyhow the key thing about this paper as I see it is the evidence for alteration in the microstructure of white matter. They give three possible explanations, with an increase in myelination suggested to fit the best both mechanistically and in relation to the imaging evaluation. This is interesting given the observations of increased brainstem volume in ME. As I indicated in my post #5, I think this points to the possibility of systemic alterations in metabolism (esp lipid metabolism) leading on to changes in myelin, that then might reflect in symptoms. Also interesting that neuroinflammation seemed not to be evidenced in this study.