Directed effective connectivity between the SCN-containing hypothalamus and pineal gland varies by chronotype in bipolar disorder
- 1University Hospital of Psychiatry Zurich
Abstract
Circadian disruption is a transdiagnostic feature of psychiatric illness, particularly in bipolar disorder (BD), where evening chronotype is linked to greater symptom severity. The suprachiasmatic nucleus (SCN) times pineal gland (PG) melatonin synthesis through a well-described feedforward pathway. Moreover, melatonin can also phase-shift the SCN-pacemaker, consistent with a functional feedback limb. Directed effective connectivity between the SCN-containing hypothalamus and the PG has not been estimated in human neuroimaging, and it is unknown whether that directed coupling varies by psychiatric diagnosis or chronotype. We applied cross-spectral dynamic causal modeling (DCM) to resting-state fMRI data in 431 UK Biobank (healthy controls [HC, N=136], BD [N=78], major depressive disorder [MDD, N=154] and psychotic disorders [PY, N=63]). Random-effects Bayesian model selection compared a fully connected model with reduced archiature and, separately, feedforward-only (SCN[->]PG) vs feedback-only (PG[->]SCN) models. A per-subject log Bayes factor difference (dF) indexed directionality preference and was tested against diagnosis, chronotype and their interaction using ANCOVA. The fully connected model was strongly preferred (posterior probability=97.8%, protected exceedance probability [PXP]=1.00). Feedforward architecture dominated overall (70% vs 30%, PXP=1.00). Diagnosis did not predict dF (p=.403), but chronotype did (p=.036), and there was a significant diagnosis-by-chronotype interaction (p<.001). Feedforward dominance was strongest in evening chronotypes (p<.001). Model evidence favored a fully connected architecture with overall feedforward dominance. That preference varied by chronotype and, qualified by the interaction, was strongest in BD evening chronotypes. The pattern supports BD-evening chronotype as a high-risk subgroup and argues for routine chronotype assessment in BD care.
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BibTeX
@misc{mehrdadi2026directed,
title = {{Directed effective connectivity between the SCN-containing hypothalamus and pineal gland varies by chronotype in bipolar disorder}},
author = {I. Mehrdadi and S. Kuster and J. Rohrer and E. Seifritz and C. Chatelain and G. Chan and P. Homan and M. Tahedl},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.26363889},
url = {https://www.medrxiv.org/content/10.64898/2026.09.24.26363889v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Directed effective connectivity between the SCN-containing hypothalamus and pineal gland varies by chronotype in bipolar disorder
AU - I. Mehrdadi
AU - S. Kuster
AU - J. Rohrer
AU - E. Seifritz
AU - C. Chatelain
AU - G. Chan
AU - P. Homan
AU - M. Tahedl
PY - 2026
DA - 2026/09/24
PB - medRxiv
DO - 10.64898/2026.09.24.26363889
UR - https://www.medrxiv.org/content/10.64898/2026.09.24.26363889v1
AB - Circadian disruption is a transdiagnostic feature of psychiatric illness, particularly in bipolar disorder (BD), where evening chronotype is linked to greater symptom severity. The suprachiasmatic nucleus (SCN) times pineal gland (PG) melatonin synthesis through a well-described feedforward pathway. Moreover, melatonin can also phase-shift the SCN-pacemaker, consistent with a functional feedback limb. Directed effective connectivity between the SCN-containing hypothalamus and the PG has not been estimated in human neuroimaging, and it is unknown whether that directed coupling varies by psychiatric diagnosis or chronotype. We applied cross-spectral dynamic causal modeling (DCM) to resting-state fMRI data in 431 UK Biobank (healthy controls [HC, N=136], BD [N=78], major depressive disorder [MDD, N=154] and psychotic disorders [PY, N=63]). Random-effects Bayesian model selection compared a fully connected model with reduced archiature and, separately, feedforward-only (SCN[->]PG) vs feedback-only (PG[->]SCN) models. A per-subject log Bayes factor difference (dF) indexed directionality preference and was tested against diagnosis, chronotype and their interaction using ANCOVA. The fully connected model was strongly preferred (posterior probability=97.8%, protected exceedance probability [PXP]=1.00). Feedforward architecture dominated overall (70% vs 30%, PXP=1.00). Diagnosis did not predict dF (p=.403), but chronotype did (p=.036), and there was a significant diagnosis-by-chronotype interaction (p<.001). Feedforward dominance was strongest in evening chronotypes (p<.001). Model evidence favored a fully connected architecture with overall feedforward dominance. That preference varied by chronotype and, qualified by the interaction, was strongest in BD evening chronotypes. The pattern supports BD-evening chronotype as a high-risk subgroup and argues for routine chronotype assessment in BD care.
ER -