Hippocampal subfield volume alterations and associations with severity measures in long COVID and ME/CFS: A 7T MRI study, 2025, Thapaliya, Barnden+

Hippocampal subfield volume alterations and associations with severity measures in long COVID and ME/CFS: A 7T MRI study
Kiran Thapaliya; Sonya Marshall-Gradisnik; Natalie Eaton-Fitch; Markus Barth; Maira Inderyas; Leighton Barnden

Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients share similar symptoms including post-exertional malaise, neurocognitive impairment, and memory loss. The neurocognitive impairment in both conditions might be linked to alterations in the hippocampal subfields. Therefore, this study compared alterations in hippocampal subfields of 17 long COVID, 29 ME/CFS patients, and 15 healthy controls (HC).

Structural MRI data was acquired with sub-millimeter isotropic resolution on a 7 Telsa MRI scanner and hippocampal subfield volumes were then estimated for each participant using FreeSurfer software.

Our study found significantly larger volumes in the left hippocampal subfields of both long COVID and ME/CFS patients compared to HC. These included the left subiculum head (long COVID; p = 0.01, ME/CFS; p = 0.002,), presubiculum head (long COVID; p = 0.004, ME/CFS; p = 0.005), molecular layer hippocampus head (long COVID; p = 0.014, ME/CFS; p = 0.011), and whole hippocampal head (long COVID; p = 0.01, ME/CFS; p = 0.01). Notably, hippocampal subfield volumes were similar between long COVID and ME/CFS patients. Additionally, we found significant associations between hippocampal subfield volumes and severity measures of ‘Pain’, ‘Duration of illness’, ‘Severity of fatigue’, ‘Impaired concentration’, ‘Unrefreshing sleep’, and ‘Physical function’ in both conditions.

These findings suggest that hippocampal alterations may contribute to the neurocognitive impairment experienced by long COVID and ME/CFS patients. Furthermore, our study highlights similarities between these two conditions.

Link | PDF (PLOS ONE) [Open Access]

 

This could explain why I went from last year uni student to having what I would even call a learning disability.

 

It doesn't look super convincing.

 

... or it might mean that being ill and having reduced activity results in larger hippocampal volumes. Cause or effect? They should check volumes in people with injuries, serious infections, etc.

 

Even if unique to ME, it may be an effect.

 

Have only skimmed bits of the paper. A couple of questions:

There were significant age differences between the 3 groups and this wasn't mentioned in the limitations section - does age not matter in this type of scan?

The graphs show that the ME group had the widest spread with the most outliers both top and bottom. Why is this group (CCC and/or ICC) less homogeneous than the more loosely diagnosed LC group?

 

HC 38.26 ± 12.74
ME 43.31 ± 11.24
LC 51.65 ± 11.26

5 years between HC and ME, but over 12 yrs between HC and LC. Hippocampal volume (overall) declines with age, so if older LC patients show increased volumes, that is probably a genuine difference that is possibly under-represented. I expect there will be differences with subfields. Some relevant recent papers are —

Hippocampal volume across age: Nomograms derived from over 19,700 people in UK Biobank (2019)

Spoiler: Abstract

Measurement of hippocampal volume has proven useful to diagnose and track progression in several brain disorders, most notably in Alzheimer's disease (AD). For example, an objective evaluation of a patient's hippocampal volume status may provide important information that can assist diagnosis or risk stratification of AD. However, clinicians and researchers require access to age-related normative percentiles to reliably categorise a patient's hippocampal volume as being pathologically small.

Here we analysed effects of age, sex, and hemisphere on the hippocampus and neighbouring temporal lobe volumes, in 19,793 generally healthy participants in the UK Biobank. A key finding of the current study is a significant acceleration in the rate of hippocampal volume loss in middle age, more pronounced in females than in males. In this report, we provide normative values for hippocampal and total grey matter volume as a function of age for reference in clinical and research settings. These normative values may be used in combination with our online, automated percentile estimation tool to provide a rapid, objective evaluation of an individual's hippocampal volume status.

The data provide a large-scale normative database to facilitate easy age-adjusted determination of where an individual hippocampal and temporal lobe volume lies within the normal distribution.

Link | PDF (NeuroImage: Clinical)

The human hippocampus and its subfield volumes across age, sex and APOE e4 status (2021)

Spoiler: Abstract

Female sex, age and carriage of the apolipoprotein E e4 allele are the greatest risk factors for sporadic Alzheimer’s disease. The hippocampus has a selective vulnerability to atrophy in ageing that may be accelerated in Alzheimer’s disease, including in those with increased genetic risk of the disease, years before onset. Within the hippocampal complex, subfields represent cytoarchitectonic and connectivity based divisions. Variation in global hippocampal and subfield volume associated with sex, age and apolipoprotein E e4 status has the potential to provide a sensitive biomarker of future vulnerability to Alzheimer’s disease.

Here, we examined non-linear age, sex and apolipoprotein E effects, and their interactions, on hippocampal and subfield volumes across several decades spanning mid-life to old age in 36 653 healthy ageing individuals. FMRIB Software Library derived estimates of total hippocampal volume and Freesurfer derived estimates hippocampal subfield volume were estimated. A model-free, sliding-window approach was implemented that does not assume a linear relationship between age and subfield volume. The annualized percentage of subfield volume change was calculated to investigate associations with age, sex and apolipoprotein E e4 homozygosity.

Hippocampal volume showed a marked reduction in apolipoprotein E e4/e4 female carriers after age 65. Volume was lower in homozygous e4 individuals in specific subfields including the presubiculum, subiculum head, cornu ammonis 1 body, cornu ammonis 3 head and cornu ammonis 4. Nearby brain structures in medial temporal and subcortical regions did not show the same age, sex and apolipoprotein E interactions, suggesting selective vulnerability of the hippocampus and its subfields.

The findings demonstrate that in healthy ageing, two factors—female sex and apolipoprotein E e4 status—confer selective vulnerability of specific hippocampal subfields to volume loss.

Link | PDF (Brain Communications) [Open Access]

Hippocampal subfield volumes across the healthy lifespan and the effects of MR sequence on estimates 92021)

Spoiler: Abstract

The hippocampus has been extensively studied in various neuropsychiatric disorders throughout the lifespan. However, inconsistent results have been reported with respect to which subfield volumes are most related to age. Here, we investigate whether these discrepancies may be explained by experimental design differences that exist between studies.

Multiple datasets were used to collect 1690 magnetic resonance scans from healthy individuals aged 18–95 years old. Standard T1-weighted (T1w; MPRAGE sequence, 1 mm 3 voxels), high-resolution T2-weighted (T2w; SPACE sequence, 0.64 mm 3 voxels) and slab T2-weighted (Slab; 2D turbo spin echo, 0.4 × 0.4 × 2 mm 3 voxels) images were included. The MAGeT Brain algorithm was used for segmentation of the hippocampal grey matter (GM) subfields and perihippocampal white matter (WM) subregions. Linear mixed-effect models and Akaike information criterion were used to examine linear, second or third order natural splines relationship between hippocampal volumes and age.

We demonstrated that stratum radiatum/lacunosum/moleculare and fornix subregions expressed the highest relative volumetric decrease, while the cornus ammonis 1 presented a relative volumetric preservation of its volume with age. We also found that volumes extracted from slab images demonstrated different age-related relationships compared to volumes extracted from T1w and T2w images.

The current work suggests that although T1w, T2w and slab derived subfield volumetric outputs are largely homologous, modality choice plays a meaningful role in the volumetric estimation of the hippocampal subfields.

Link (NeuroImage)

Age differences in hippocampal subfield volumes from childhood to late adulthood (2016)

Spoiler: Abstract

The hippocampus is composed of distinct subfields: the four cornu ammonis areas (CA1-CA4), dentate gyrus (DG), and subiculum. The few in vivo studies of human hippocampal subfields suggest that the extent of age differences in volume varies across subfields during healthy childhood development and aging. However, the associations between age and subfield volumes across the entire lifespan are unknown.

Here, we used a high-resolution imaging technique and manually measured hippocampal subfield and entorhinal cortex volumes in a healthy lifespan sample (N = 202), ages 8–82 yrs. The magnitude of age differences in volume varied among the regions. Combined CA1-2 volume evidenced a negative linear association with age. In contrast, the associations between age and volumes of CA3-DG and the entorhinal cortex were negative in mid-childhood and attenuated in later adulthood. Volume of the subiculum was unrelated to age.

The different magnitudes and patterns of age differences in subfield volumes may reflect dynamic microstructural factors and have implications for cognitive functions across the lifespan.

Link | PDF (Hippocampus)

 

One consideration might be the ApoE4 status if that turned out to be different between the two groups. From the reference above —

 

ME Research UK:

Kiran Thapaliya and colleagues from Griffith University recently published another paper from their ME Research UK-funded brain imaging project, this time looking at alterations in the hippocampus in ME/CFS and long COVID.

You can now read a more detailed explanation of their findings on our website: bit.ly/40EtMjk