# Altered putamen connectivity in patients with neurological post-COVID condition

## TL;DR

This study finds that patients with post-COVID symptoms have altered brain connectivity in the putamen, which is linked to fatigue severity.

## Contribution

The study is the first to investigate the structural connectome in post-COVID patients, revealing putamen connectivity changes associated with fatigue.

## Key findings

- Putamen node strength is significantly increased in post-COVID patients and correlates with fatigue severity.
- Putamen betweenness centrality is elevated in post-COVID patients but not linked to fatigue or cognitive performance.
- Structural connectome alterations in the putamen may contribute to post-COVID fatigue.

## Abstract

Although the exact aetiology of the post-COVID condition is still under investigation, there is increasing evidence for white matter pathology in patients with persistent cognitive and fatigue symptoms following an infection with SARS-CoV-2. Still, to date there are no studies that investigated the white matter connectome in patients with post-COVID condition. Based on previous findings, we analyzed the structural connectome of these patients, with a focus on the thalamus and basal ganglia. In this cross-sectional study, 43 patients (34 women, 9 men) and 41 (33 women, 8 men) healthy control participants underwent structural MRI, including T1-weighted and diffusion weighted imaging, as well as a comprehensive neuropsychological and psychiatric assessment. The cognitive assessment included verbal and visual long-term memory, working memory, attention, processing speed, executive control, verbal fluency and spatial navigation. Fatigue was assessed with the Fatigue Scale for Motor and Cognitive Functions, depression and anxiety were assessed with the Beck Depression Inventory II and the Beck Anxiety Inventory, respectively. MRI data was analyzed using probabilistic tractography, reconstructing 100 million streamlines per participant, to create individual connectomes. Connectome alterations were assessed using graph theory by calculating node strength and betweenness centrality for the thalamus and basal ganglia. We then analyzed group differences in these measures between patients and control participants with the Mann–Whitney-U-test. For significant alterations, we explored associations between graph measures, fatigue and cognition, depression and anxiety using spearman correlations. We identified significantly increased node strength of the putamen (U = 589, pFDR = 0.036), which was significantly associated with the fatigue severity in patients (ρ = 0.33, P = 0.045) but not in control participants (ρ = 0.11, P = 0.509). Betweenness centrality of the putamen was increased in patients with post-COVID condition (U = 620, P = 0.019) but was not associated with fatigue (ρ = 0.07, P = 0.685). Neither node strength nor betweenness centrality of the putamen was associated with cognitive performance, depression or anxiety scores. Patients with post-COVID condition exhibit structural connectome alterations that are associated with fatigue severity. Such structural white matter pathology may thus contribute to post-COVID pathophysiology. In addition, putamen connectivity could be a neural correlate of post-COVID fatigue.

White matter pathology is one possible mechanism underlying post-COVID symptoms. Schlenker et al. investigated the structural connectome in patients with post-COVID-condition, focusing on the basal ganglia and thalamus. They found altered connectivity of the putamen, which was associated with fatigue but not cognitive dysfunction.

Graphical Abstract