Table 1.
MRI studies investigating the role of the brainstem in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
| References | Sample (N) | Mean age ± SD | Design | Structural MRI | Functional MRI | Main findings |
|---|---|---|---|---|---|---|
| Barnden et al. (36)* | ME/CFS (25) M: F = 6:19 HC (25) M: F = 6:19 |
ME/CFS = 31.7 ± 8.8 HC = 33.7 ± 10.3 |
Cross-sectional case-controlled study | 1.5T; T1W imaging spin-echo; T2W imaging spin-echo; 3D spoiled-GRE | None | (1) No regional or global group mean differences in T1W or T2W signal levels, or gray matter (GM) or white matter (WM) volumes (2) Group differences in correlations between structural (e.g., brainstem GM volume; pons, prefrontal cerebellar vermis, and hypothalamus WM volumes, brainstem and cerebellum T1W signal level—suggestive of myelination level) and physiological measures [e.g., seated pulse pressure (PP), diastolic blood pressure (BP), and asleep heart rate (HR)] in multiple brain regions in ME/CFS compared to HC (3) Midbrain WM volume decreased with increasing illness duration in ME/CFS |
| Barnden et al. (37)* | ME/CFS (25) M: F = 6:19* HC (25). M: F = 6:19* |
ME/CFS = 32* HC = 32.8* |
Cross-sectional case-controlled study; voxel-based analysis | 1.5T; T1W imaging spin-echo; T2W imaging spin-echo; 3D spoiled-GRE | None | (1) Midbrain WM volume decreased with increasing illness duration in ME/CFS (2) T1W signal level increased (suggestive of increased myelination) in ventrolateral thalamus, internal capsule, and prefrontal with increasing ME/CFS symptom severity, presumably in compensation of the midbrain impairment (3) T2W signal level increased (suggestive of decreased regional blood volume) with increasing illness duration in right middle temporal WM in ME/CFS compared to HC |
| Barnden et al. (38)* | ME/CFS (25) M: F = 6:19* HC (25) M: F = 6:19* |
ME/CFS = 32* HC = 32.8* |
Cross-sectional case-controlled study | 1.5T; T1W imaging spin-echo; T2W imaging spin-echo; 3D spoiled-GRE | None | (1) No regional group differences in T1W or T2W signal levels, or GM or WM volumes in the abnormally correlated brain areas (2) Opposite correlation patterns between multiple MRI measures in focal brainstem structures (e.g., medulla T2W signal level; pons WM volume; hypothalamus T1W signal level and WM volume; cuneiform nucleus and ventral tegmental T1W signal level) and several physiological measures (e.g., erect PP and BP; reclined systolic BP and HR) in ME/CFS compared to HC |
| Finkelmeyer et al. (39) | ME/CFS (42) M: F = 10:32 HC (30) M: F = 9:19 |
ME/CFS = 45.6 ± 11.7 HC = 48.4 ± 11.3 |
Cross-sectional study; whole-brain and voxel-wise GM and WM volume analysis | 3.0T; T1W imaging MPRAGE | None | (1) Reduced group mean WM volume in midbrain, pons, internal and external capsules, prefrontal, inferior frontal, and temporal lobe in ME/CFS compared to HC (2) Increased group mean GM volume in parts of the inferior frontal, occipital and temporal lobes, putamen, thalamus, amygdala, and hippocampus in ME/CFS compared to HC (3) Reduced total intracranial volume (TIV), increased TIV-adjusted global GM volume, and decreased TIV-adjusted global WM volume in ME/CFS compared to HC (4) Negative associations between symptom severity and TIV, TIV-unadjusted GM, and cerebrospinal fluid volume in ME, not in HC |
| Barnden et al. (40)** | ME/CFS (43) M: F = N/A** HC (27) M: F = N/A** |
Not available** | Cross-sectional study | 3.0T; T1W imaging spin-echo; T2W imaging spin-echo | None | (1) Decreased T1W signal levels (suggestive of decreased myelination) in brainstem (ventral tegmental, pontine nuclei, medulla regions), and increased T1W signal levels in cortical WM regions (premotor and sensorimotor cortices) in ME/CFS compared to HC (2) In both ME/CFS and HC, there was a negative correlation between the T1W signal levels in the sensorimotor cortex (high myelination) and brainstem (low myelination) |
| Boissoneault et al. (41) | ME/CFS (19) M: F = 0:19 HC (15) M: F = 0:15 |
ME/CFS = 48.3 ± 12.2 HC = 47.9 ± 12.1 |
Cross-sectional study | 3.0T; T1W imaging MPRAGE | fMRI (ASL): resting & PASAT task | (1) Increased functional connectivity (FC) between inferior frontal gyrus and the brainstem and several other brain areas (lingual gyrus, cerebellar vermis, cerebellum, and parahippocampal gyrus) from start to end of the task in ME/CFS but decreased in HC. (2) Greater increases in FC between these areas were positively associated with greater fatigue level (i.e., more fatigued toward the end of the task) |
| Barnden et al. (42)** | ME/CFS (45) M: F = N/A** HC (27) M: F = N/A** |
Not available** | Cross-sectional study | 3.0T; T2W imaging “SPACE” optimized 3D fast spin-echo | fMRI (EPI): resting & Stroop task | (1) Deficits in the FC between cuneiform nucleus and medulla, and between brainstem and hippocampus and intralaminar thalamus during the task in ME (2) Reduced connectivity in ME/CFS was associated with increased symptom severity |
| Thapaliya et al. (43)** | ME/CFS (45) M: F = 12:33** HC (27) M: F = 9:18** |
ME/CFS = 47.1 ± 11.7** HC = 43.1 ± 13.7** |
Cross-sectional; T1W/T2W ratio assessment | 3.0T; T1W imaging MPRAGE; T2W imaging “SPACE” optimized 3D fast spin-echo | None | (1) Increased T1W/T2W ratio (indicative of higher levels of myelin and/or iron) in 16 WM regions (i.e., left and right corticospinal tract, left medial lemniscus, right anterior and left and right posterior limbs of internal capsule, left and right anterior, superior, and posterior corona radiata, left cingulum, forceps minor, sensorimotor, and right inferior longitudinal fasciculus) in ME/CFS compared to HC (2) Increased T1W/T2W ratio in 4 subcortical GM regions (i.e., left and right putamen and pallidum) in ME/CFS compared to HC (3) Voxel-based analysis detected 7 significant clusters with T1W/T2W greater in ME/CFS [globus pallidus, paracentral lobule, posterior corona radiata, left precuneus, putamen, cerebrospinal tract (pons) and medial lemniscus (pons)], consistent with the region findings in 1) (4) Clinical and functional measures (i.e., heart rate variability, SF36 physical, respiratory rate, Stroop Effect) correlated with abnormal T1W/T2W ratio in several brain regions (e.g., cingulate and middle temporal gyri, cerebral WM) in ME/CFS (5) No ME/CFS regions had decreased T1W/T2W ratio compared to HC. |
| Manca et al. (44) | ME/CFS (6) M: F = 0:6 HC (10) M: F = 0:10 |
ME/CFS = 42.8 ± 5.7 HC = 39.3 ± 8.7 |
Repeated measure of MRI; pilot study with 2 scans several days apart | 3.0T; T1W imaging MPRAGE; T2-FLAIR |
fMRI (EPI): resting | (1) No regional or global group mean differences in GM, WM, or WM hyperintensity volumes (2) Altered baseline FC between default mode network seeds (right inferior parietal lobules and posterior cingulate cortex) and frontal areas (left and right superior frontal gyrus and left precentral gyrus) in ME/CFS compared to HC (3) Greater baseline FC between salience network seeds (anterior cingulate, right and left insula) and left superior temporal gyrus; and between both insulae and the medulla and cerebellar tonsil in ME/CFS compared to HC (4) Post cognitive exertion, increased FC between right insula and several brain areas (orbito-frontal cortex, thalamus, hypothalamus, and basal ganglia) in ME/CFS compared to HC, with increased fatigue negatively associated with decreased FC between right insula and right inferior temporo-occipital areas; and increased pain associated with altered FC between right insula and several frontal areas (e.g., superior temporal gyrus, inferior frontal gyrus, frontal pole) in ME/CFS. |
| Addiego et al. (45) | ME/CFS (38) M: F = 11:27 GWI (90) M: F = 70:20 HC (34) M: F = 22:12 |
ME/CFS = 47.7 ± 13.0 GWI = 47.5 ± 7.5 HC = 43.7 ± 16.6 |
Cross-sectional study; volumetric analysis | 3.0T; T1W imaging MPRAGE | None | (1) Decreased adjusted volume for left putamen, right caudate and left cerebellum WM in ME/CFS compared to HC (2) In ME/CFS, brainstem volume correlated with several brain region volumes (left and right ventral diencephalon, right pallidum, and left cerebellum WM) (3) In HC, brainstem volume correlated with several other brain region volumes (right hippocampus and caudate, left and right diencephalon, thalamus, cerebellum cortex, and pallidum) |
| Thapaliya et al. (46)** | ME/CFS-F (25) M: F = 5:20** ME/CFS-ICC (18) M: F = 6:12** HC (26) M: F = 9:17** |
ME/CFS-F = 49.8 ± 12.2** ME/CFS-ICC = 43.3 ± 10.7** HC = 43.1 ± 13.7** |
Cross-sectional study | 3.0T; DTI | None | (1) Decreased DTI parameters [i.e., axial diffusivity, mean diffusivity, mode of anisotropy, transverse eigenvalue (λ2)] in several brain regions (i.e., midbrain/pons, superior longitudinal fasciculus) in ME-ICC compared to HC (2) Increased DTI parameter (λ3) in medulla in ME-ICC compared to HC (3) No group difference in DTI parameters in any brain regions between ME-F and HC (4) Opposite correlation patterns between ME-ICC and HC in DTI parameters (i.e., fractional anisotropy, axial diffusivity, mean diffusivity, radial diffusivity, mean of anisotropy) of several brain regions (e.g., parahippocampal gyrus, corpus callosum, hippocampus, posterior cingulate, external capsule) vs. clinical measures (e.g., information processing score, respiratory rate, SF36 physical, sleep disturbance score) |
*
Indicating same cohort and data is available in another Table entry (1).
**
Indicating that these entries mostly applied the same cohort as Table entry (8). M: F, males: females; MRI, magnetic resonance imaging; SD, standard deviation; ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome; M, male; F, female; HC, healthy control; T1W, T1-weighted; T2W, T2-weighted; GRE, gradient echo; GM, gray matter; WM, white matter; PP, pulse pressure; BP, blood pressure; HR, heart rate; MPRAGE, magnetization prepared rapid gradient echo; TIV, total intracranial volume; fMRI, functional magnetic resonance imaging; ASL, arterial spin labeling; PASAT, Paced Auditory Serial Addition Test; FC, functional connectivity; SPACE, Sampling Perfection with Application optimized Contrast; EPI, echo-planar imaging; T2-FLAIR, T2-weighted Fluid-Attenuated Inversion Recovery; GWI, Gulf War Illness; ME/CFS-F, ME/CFS Fukada criteria; ME/CFS-ICC, ME/CFS International Consensus Criteria.