Authors
Leah J Hudson, Christopher G Davey, Trevor Steward, Po-Han Kung, Yingliang Dai, Lee Unsworth, Alec J Jamieson, Bradford A Moffat, Rebecca Glarin, Ben J Harrison
Published in
The Journal of neuroscience : the official journal of the Society for Neuroscience. Oct 29, 2026. Epub Oct 29, 2026.
Abstract
The habenula is implicated in signaling negative reward prediction errors (RPE), yet direct evidence demonstrating its influence on downstream human brain circuits is limited. Using ultra-high field (7T) fMRI and dynamic causal modelling across two negative RPE-inducing experimental tasks, we characterize habenula-directed connectivity with monoaminergic midbrain and cortical pathways in healthy adults (n = 47, 24 males and 23 females; n = 43, 23 males and 20 females). Negative feedback drove habenula inhibition of ventral tegmental area and dorsal raphe nucleus activity, while positive feedback had an excitatory effect. These core effects are replicated across reversal learning and perceptual decision uncertainty tasks, establishing a generalizable mechanism for behavioral adaptation. Task-specific modulatory effects emerged in pathways between the subcortical and cortical regions (ventral tegmental area→dorsal anterior cingulate cortex, dorsal raphe nucleus→medial prefrontal cortex, and dorsal anterior cingulate cortex→habenula), revealing context-dependent cortical elaboration of negative RPE-driven habenula signals. This provides the first evidence in humans, using model-based effective connectivity, for bivalent modulation of habenula function on monoaminergic midbrain and cortical pathways, demonstrating how the brain integrates negative and positive signals to guide adaptive behavior.Significance Statement The habenula - an epithalamic brain region - plays a key role in the encoding of reward and punishment. Animal studies have demonstrated the habenula to be bivalently modulated by aversive and appetitive stimuli, resulting in the bidirectional modulation of monoaminergic brain region activity. Despite this evidence, the directional impact of bivalently modulated habenula activity on its circuitry has yet to be investigated in humans. This study leverages ultra-high field (7T) fMRI and dynamic causal modelling to reveal the impact of bivalent habenula modulation on monoaminergic midbrain and cortical regions across two distinct tasks. Through these methodologies, we demonstrate the habenula to have a key role in guiding adaptive behavior.
PMID:
42957319
Bibliographic data and abstract were imported from PubMed on 30 Oct 2026.
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