3636
Hippocampal subfield volumes exhibit differences in ME/CFS and are associated with clinical measures1Menzies Health Queensland, NCNED, Griffith University, Southport, Australia, 2Centre for Advanced Imaging, The University of Queensland, St Lucia, Australia
Synopsis
Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients suffer from a variety of physical and neurological complaints indicating involvement of the central nervous system including cognitive and memory dysfunction along with a variety of disabling physical symptoms. The hippocampus plays a key role in cognitive function and is altered in neurodegenerative diseases. In this study, we evaluated the volumetric changes in the subfields of the hippocampus in ME/CFS and performed a correlation between hippocampal subfield volumes and clinical measures. Our study showed that hippocampal subfield volumes were lower/higher in ME/CFS patients compared with healthy controls and are also associated with clinical measures
Introduction
Myalgic Encephalomyelitis/ Chronic fatigue syndrome (ME/CFS) is a complex illness characterised by profound fatigue for more than 6 months that impairs cognitive and motor dysfunction, and unrefreshing sleep1. Patients who suffer from ME/CFS report a variety of physical complaints as well as neurological symptoms such as cognitive impairment,and loss of memory and concentration. MRI studies have been conducted based on the white matter hyperintensities (WMH), volume-based analysis (increase in ventricular volume, decrease in brain and white matter volume)2,3, and BOLD studies4 to find the definite marker for underlying causes of ME/CFS. ME/CFS patients have also shown volumetric changes in the cerebral cortex regions5. The hippocampus is an extension of the temporal lobe of the cerebral cortex6 and plays an important role in cognitive functions such as memory, executive processing, and reward processing7. Saury8 described the role of the hippocampus in neurocognitive deficits, disturbance in the regulation of stress response, and pain perception in ME/CFS. It has been reported that 89% of ME/CFS patients have memory and concentration problems, and difficulties in processing complex information9. However, no previous study has investigated volumetric changes in the subfields of the hippocampus in ME/CFS patients. Therefore, the specific aim of this preliminary study was a) to estimate the subfield volumes of the hippocampus in ME/CFS patients and compare with healthy controls, and b) investigate the relationship between hippocampal subfields volumes and clinical measures of ME/CFS patients.Methods
The study was approved by the local human ethics (HREC/15/QGC/63 and GU:2014/838) committee of Griffith University and the Gold Coast University Hospital where scanning was performed. Written informed consent was obtained from 16 ME/CFS patients, meeting ICC criteria, and 26 gender-matched healthy controls. The T1-weighted data were acquired using a 3T Skyra MRI scanner (Siemens Healthcare, Erlangen, Germany) with a 64-channel head-neck coil (Nova Medical, Wilmington, USA). Three-dimensional anatomical images were acquired using a T1-weighted magnetization prepared rapid gradient-echo (MPRAGE) sequence with a repetition time (TR) = 2400 ms, echo time (TE) = 1.81 ms, flip-angle = 8°, acquisition matrix = 224×224×208, and voxel size 1mm3. T1 MPRAGE images were anatomically segmented using the FreeSurfer version 7.1.110 (https://surfer.nmr.mgh.harvard.edu/) using the default FreeSurfer command ‘recon-all’ on the Macintosh computer (Operating system: Catalina, RAM=36GB, and core: 8). The ‘recon-all’ processing includes motion correction, non-linear spatial normalization, automated Talairach transformation, intensity normalisation, removal of non-brain tissue, cortical parcellation, sub-cortical segmentation, grey and white matter boundary tessellation, automated topology correction, and surface deformation. Hippocampus subfield segmentation was generated via the Free-surfer 7.1.1 hippocampus subfield module11 as shown in Figure 1. Using this module, the left and right hippocampal subfield head, body, and tail; parasubiculum, presubiculum, subiculum, coronis ammonis (CA1, CA3, and CA4); granule cell layers of the dentate gyrus (GC-ML-DG), molecular layer of the hippocampus, fissure, fimbria, and hippocampus-amygdala transition area (HATA) were obtained. The intracranial volume of each subject was calculated. The multivariate analysis of covariance (MANCOVA) test was performed to test hippocampal subfield volume differences between ME/CFS patients and healthy controls using SPSS version 27. Furthermore, Spearman’s correlations were performed between the hippocampal subfield volumes and clinical measures for ME/CFS defined patients. Age, gender, and intracranial volume (ICV) were used as covariates for group comparison and correlation analysis, and multiple comparisons were corrected using Bonferroni correction.Results
We compared hippocampal subfield volumes between ME/CFSICC and HC. We found three subfield volumes were significantly reduced in ME/CFS patients: the left CA1 body (p=0.012), CA1 head (p=0.013) and CA3-body (p=0.026) (see Table 1). Four of the subfield volumes were significantly larger in ME/CFS patients compared with HC: the left and right subiculum head (left: p<0.001; right: p=0.008), left presubiculum (p=0.20), and left fimbria (p=0.004) (see Table 1). We observed a statistically significant relationship between ‘fatigue’ and left hippocampal tail volume (r=-0.803, p=0.016) which implies more severe fatigue is associated with smaller volume (see figure 2). The ‘information processing score’ clinical measure showed strong positive associations with volumes (see Figure 3) of the left subiculum head (r=0.715, p=0.009) and right subiculum head (r=0.817, p=0.001). We observed a strong, negative relationship between ‘pain’, left GC-ML-DG-head (r=-0.67, p=0.016), and left CA4 head volume (r=-0.65, p=0.022). The negative association between subfield volumes and pain implies that smaller volume is related to higher pain levels (see Figure 3).Dicussion
Our study found hippocampal subfield volumes exhibited differences in ME/CFS compared with healthy controls and are strongly associated with fatigue, information processing, and pain score. In neurodegenerative diseases, smaller subfield volumes were reported in Alzheimer’s Disease and schizophrenia compared with healthy controls12,13. The larger subiculum and presubiculum in ME/CFS patients suggest ME/CFS is a neuroregulatory rather than a neurodegenerative response. We also showed hippocampal subfield volumes were associated with pain, information processing score, and fatigue which has also been reported in human studies14–16.Conclusion
In this study, we investigated hippocampal subfield volumes in ME/CFS patients and healthy controls. We observed smaller/or larger hippocampal subfield volumes in ME/CFS compared with healthy controls. Clinical measures related to cognitive function (procinfo), pain, and fatigue showed a strong relationship with hippocampal subfield volumes in the ME/CFS patients.Acknowledgements
We thank the patients and healthy controls who donated their time and effort to participate in this study. This study was supported by the Stafford Fox Medical Research Foundation, the Judith Jane Mason Foundation (MAS2015F024), Mr. Douglas Stutt, and the Blake-Beckett Foundation. The financial support did not affect any aspect of the study.References
1. Fukuda, K. The Chronic Fatigue Syndrome: A Comprehensive Approach to Its Definition and Study. Ann. Intern. Med. 121, 953 (1994).
2. Lange, G. et al. Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. J. Neurol. Sci. 171, 3–7 (1999).
3. Lange, G. et al. Quantitative assessment of cerebral ventricular volumes in chronic fatigue syndrome. Appl. Neuropsychol. 8, 23–30 (2001).
4. Barnden, L. R. et al. Intra brainstem connectivity is impaired in chronic fatigue syndrome. NeuroImage Clin. 24, 102045 (2019).
5. Maksoud, R. et al. A systematic review of neurological impairments in myalgic encephalomyelitis/ chronic fatigue syndrome using neuroimaging techniques. PLOS ONE 15, e0232475 (2020).
6. Gilbert, P. E. & Brushfield, A. M. The role of the CA3 hippocampal subregion in spatial memory: a process oriented behavioral assessment. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 774–781 (2009).
7. Brown, A. A., Jason, L. A., Evans, M. A. & Flores, S. Contrasting Case Definitions: The ME International Consensus Criteria vs. the Fukuda et al. CFS Criteria. North Am. J. Psychol. 15, 103–120 (2013).
8. Saury, J.-M. The role of the hippocampus in the pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Med. Hypotheses 86, 30–38 (2016).
9. Jason, L. A. et al. Contrasting case definitions for chronic fatigue syndrome, myalgic encephalomyelitis/chronic fatigue syndrome and myalgic encephalomyelitis. Eval. Health Prof. 35, 280–304 (2012).
10. Fischl, B. FreeSurfer. NeuroImage 62, 774–781 (2012).
11. Iglesias, J. E. et al. A computational atlas of the hippocampal formation using ex vivo, ultra-high resolution MRI: Application to adaptive segmentation of in vivo MRI. NeuroImage 115, 117–137 (2015). 12. Carlesimo, G. A. et al. Atrophy of presubiculum and subiculum is the earliest hippocampal anatomical marker of Alzheimer’s disease. Alzheimers Dement. Diagn. Assess. Dis. Monit. 1, 24–32 (2015).
13. Haukvik, U. K. et al. In vivo hippocampal subfield volumes in schizophrenia and bipolar disorder. Biol. Psychiatry 77, 581–588 (2015).
14. Zimmerman, M. E. et al. Hippocampal correlates of pain in healthy elderly adults: a pilot study. Neurology 73, 1567–1570 (2009).
15. Thapaliya, K., Marshall-Gradisnik, S., Staines, D. & Barnden, L. Diffusion tensor imaging reveals neuronal microstructural changes in myalgic encephalomyelitis/chronic fatigue syndrome. Eur. J. Neurosci. 54, 6214–6228 (2021).
16. Wasson, E. et al. Neural correlates of perceived physical and mental fatigability in older adults: A pilot study. Exp. Gerontol. 115, 139–147 (2019).
Figures
