Circadian-Related Hypothalamic Structure Differs by Chronotype in Bipolar Disorder

Circadian rhythm disturbances represent a core feature of bipolar disorder (BD), with evening chronotype as a marker for poorer outcomes. We hypothesized that BD psychopathology combined with evening chronotype would be associated with structural alterations in circadian-related hypothalamic regions, particularly the suprachiasmatic nucleus (SCN), specific to BD relative to other psychiatric diagnoses.

We investigated structural neuroimaging data from the UK Biobank (113 BD, 205 major depressive disorder, 91 psychotic disorders, 199 healthy control). The SCN-containing anterior-inferior hypothalamic subunit was segmented, central to circadian functional neuroanatomy. For each group, the effect of diagnosis × chronotype interactions on its volume were tested using analysis of variance, with post hoc estimated marginal means and correction for multiple comparisons. Covariates included age, sex, handedness, and psychiatric medication use. Specificity was examined across 4 additional hypothalamic subunits.

There was a diagnosis × chronotype interaction in the SCN-containing anterior-inferior hypothalamic subunit volume (F_6,586 = 2.84, p = .010). This was driven by larger volumes in individuals with BD with evening versus morning chronotype (t₅₈₆ = 3.24, familywise error rate-corrected p = .004). No comparable results were found in other hypothalamic regions or diagnoses.

Hypothalamic structure differs by chronotype in BD, with chronotype-related associations localized to an anterior-inferior hypothalamic region implicated in circadian regulation. These findings support chronotype as a biologically meaningful dimension of variation in BD and provide neuroanatomical evidence linking circadian preference to circadian-relevant brain structure. Longitudinal and interventional studies will be important to clarify the temporal dynamics, underlying mechanisms, and potential clinical significance of these associations.