Hypothalamus volumes in adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): impact of self-reported fatigue and illness duration

Abstract

Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex illness of unknown aetiology. Emerging theories suggest ME/CFS may reflect a progressive, aberrant state of homeostasis caused by disturbances within the hypothalamus, yet few studies have investigated this using magnetic resonance imaging in adolescents with ME/CFS. We conducted a volumetric analysis to investigate whether whole and regional hypothalamus volumes in adolescents with ME/CFS differed compared to healthy controls, and whether these volumes were associated with fatigue severity and illness duration. 48 adolescents (25 ME/CFS, 23 controls) were recruited. Lateralised whole and regional hypothalamus volumes, including the anterior-superior, superior tubular, posterior, anterior-inferior and inferior tubular subregions, were calculated from T1-weighted images. When controlling for age, sex and intracranial volume, Bayesian linear regression models revealed no evidence for differences in hypothalamus volumes between groups. However, in the ME/CFS group, a weak linear relationship between increased right anterior-superior volumes and fatigue severity was identified, which was absent in controls. In addition, Bayesian quantile regression revealed a likely-positive association between illness duration and right superior tubular volumes in the ME/CFS group. While these findings suggest overall comparability in regional and whole hypothalamus volumes between adolescents with ME/CFS and controls, preliminary evidence was identified to suggest greater fatigue severity and longer illness duration were associated with greater right anterior-superior and superior-tubular volumes, respectively. These regions contain the anterior and superior divisions of the paraventricular nucleus, involved in the neuroendocrine response to stress, suggesting involvement in ME/CFS pathophysiology. However, replication in a larger, longitudinal cohort is required.

Keywords: Adolescence; Chronic Fatigue Syndrome; Hypothalamus; Myalgic Encephalomyelitis; Structural magnetic resonance imaging; Volumetric analysis.

Fig. 1

Sagittal (a), coronal (b) and axial (c) views of an example hypothalamus segmentation obtained from a participant. a Right anterior–superior (dark blue), right anterior-inferior (light blue), right inferior tubular (yellow), right superior tubular (orange) and right posterior (dark orange); b superior tubular (light orange), right inferior tubular (dark yellow), left inferior tubular (blue); c right posterior (dark orange), right superior tubular (light orange), right anterior–inferior (light blue), left anterior–inferior (light yellow), left superior tubular (dark blue), left posterior (turquoise). Coronal and axial images are right–left reversed as per acquisition (R→L)

Fig. 2

Jitter plots showing raw (uncorrected) whole left (a) and right (b) hypothalamus volumes for each group and their estimated marginal means with corresponding 95% upper and lower confidence intervals (bars)

Fig. 3

a Scatter plot showing relationship between raw (uncorrected) right anterior–superior volumes and Total Fatigue scores by group; b marginal means plot showing relationship and trend lines between corrected right anterior–superior volumes and Total Fatigue by group. Note higher subscale scores indicate fewer symptoms of fatigue

Fig. 4

a Jitter plot showing raw (uncorrected) right superior tubular volumes for the ME/CFS group with increasing illness duration, and b plot showing right superior tubular volumes corrected for age, sex and eTIV over illness duration with 95% Credible Interval bars