2026 ECNP Congress

PS04-4036

Linking locus coeruleus (LC) integrity and reward-associated pupil dilation to understand anhedonia in major depressive disorder (MDD)

Andy Brendler — L. Hartinger, T. Brückl, E. Binder, M. Czisch, V.I. Spoormaker, P.G. Sämann · Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, Munich, Germany

2026 ECNP Congress

Background

Anhedonia – a core symptom in Major Depressive Disorder (MDD) that is still incompletely understood at the neurobiological level - has been linked to worse clinical trajectories [1]. In earlier work on MDD, we have identified a blunted arousal upregulation as candidate mechanism for anhedonia symptomology, reflected in reduced pupil dilation and BOLD activity in the salience network , likely reflecting a reduced locus coeruleus –norepinephrine (LC/NE) system activation [2]. However, to which extent these findings relate directly to more downstream arousal source areas such as the LC remained unclear. Here, we build on this by including an LC integrity MRI marker and its influence on the LC/NE arousal system in anhedonia. We examined if the diminished reward related pupil response relates to LC integrity as quantified by a proxy marker from routine T1-weighted imaging. Furthermore, we explored to which extent this relationship was modulated by anhedonia and overall depression in MDD.

Methods

We analyzed pupil dilation and T1-weighted imaging data from a total of 200 participants from the biological classification of mental disorders (BeCOME) study [3],who performed a reward anticipation task. It was ensured that only unmedicated MDD patients (n= 117, age range: 18- 65years, age M = 35.5, SD = 13.1, 36women) and healthy controls (n= 83, age range: 20 - 62years, age M = 33.7, SD = 12.3, 37women) were included. LC integrity values were defined as average intensity on routine T1-images (General Electric, MR750, 3 Tesla, BRAVO sequence, 1x1x1 mm3) within an LC-mask created from a neuromelanin sensitive images sequence of 47 independent patients (MPIP Biobanking study). For both samples, CAT12 and geodesic shooting were used for bias correction, optimal intersubject coregistration and T1-intensity normalization [4, 5]. Based on BDI-II anhedonia and total scores, we further defined low (0-4) and high (5-9) anhedonia levels and low (0-13), intermediate (14-28) and high (> 29) depression severity levels. We fitted three models using ordinary least squares regression to examine whether LC integrity predicted pupil dilation, controlling for age and sex. Furthermore, we investigated if this relationship was moderated by anhedonia and depression severity.

Results

We found a positive association at trend-level between LC integrity and pupil dilation (p = 0.068), with age showing a negative covarying correlation (p < 0.009). This association was significant when accounting for anhedonia severity level (p = 0.027). The LC-by-anhedonia interaction reached trend-level significance (p = 0.073). There was no significant LC effect or interaction with depression severity, however, higher depression severity was associated with reduced pupil dilation at trend-level (p = 0.050).

Conclusions

We suggest that our earlier finding of attenuated reward-related pupil responses in MDD could in part be mediated by changes of the LC/NE system as measured by a proxy-LC-integrity marker extracted from (routine) T1-weighted images. Replications using explicit neuromelanin sensitive imaging are needed.

References

  1. Wu, C., Mu, Q., Gao, W., & Lu, S. (2025). The characteristics of anhedonia in depression: a review from a clinically oriented perspective. Translational Psychiatry, 15(1), 90.
  2. Brendler, A., Schneider, M., Elbau, I. G., Sun, R., Nantawisarakul, T., Pöhlchen, D., Brückl, T., BeCOME Working Group, Czisch, M., Sämann, P. G., Lee, M. D. & Spoormaker, V. I. (2024). Assessing hypo-arousal during reward anticipation with pupillometry in patients with major depressive disorder: replication and correlations with anhedonia. Scientific Reports, 14(1), 344.
  3. Brückl, T. M., Spoormaker, V. I., Sämann, P. G., Brem, A. K., Henco, L., Czamara, D., … & Binder, E. B. (2020). The biological classification of mental disorders (BeCOME) study: a protocol for an observational deep-phenotyping study for the identification of biological subtypes. BMC psychiatry, 20(1), 213.
  4. Galgani, A., Lombardo, F., Della Latta, D., Martini, N., Bonuccelli, U., Fornai, F., & Giorgi, F. S. (2021). Locus coeruleus magnetic resonance imaging in neurological diseases. Current Neurology and Neuroscience Reports, 21(1), 2.
  5. Plini, E. R., Melnychuk, M. C., Andrews, R., Boyle, R., Whelan, R., Spence, J. S., … & Dockree, P. M. (2024). Greater physical fitness (VO 2 max) in healthy older adults associated with increased integrity of the locus coeruleus–noradrenergic system. Acta Physiologica, 240(8), e14191.