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Peer-reviewedCC BY 4.0CNS Spectrums

Metabolic dysfunction-associated steatotic liver disease and neurocognitive and reward circuit dysfunction: implications for mental disorders

  • Nina Sachi Mollin1,2
  • Gia Han Le2,3
  • Christine E. Dri2
  • Elim Yang1
  • Folkert van Bruggen4
  • Kangguang Lin5
  • Stavroula Bargiota6
  • Heidi K.Y. Lo7
  • Roger Ho8
  • Taeho Greg Rhee9
  • Bing Cao10
  • Angela T.H. Kwan2
1 more authors
  • Roger S. McIntyre11,12
12 affiliations
  1. 1University of Toronto, Canada
  2. 2Brain and Cognition Discovery Foundation, Canada
  3. 3University of Toronto Institute of Medical Science, Canada
  4. 4University Medical Center Groningen Department of Primary and Long-term Care, Netherlands
  5. 5Department of Psychiatry and Behavioral Sciences, The Chinese University of Hong Kong Faculty of Medicine, Hong Kong
  6. 6Department of Psychiatry, University of Thessaly School of Health Sciences, Greece
  7. 7The University of Hong Kong Department of Psychiatry, Hong Kong
  8. 8National University of Singapore Yong Loo Lin School of Medicine, Singapore
  9. 9Psychiatry, Yale University School of Medicine, USA
  10. 10Southwest University, China
  11. 11Department of Pharmacology and Toxicology, University of Toronto, Canada
  12. 12Department of Psychiatry, University of Toronto, Canada
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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) (formerly known as nonalcoholic fatty liver disease) is the most prevalent liver disease globally. Emerging evidence suggests MASLD-related metabolic and inflammatory processes may disrupt frontostriatal–limbic circuits, contributing to alterations in cognitive and reward-related brain function. This systematic review aimed to examine whether MASLD is associated with changes in cognitive functioning and reward-related processes, and whether these changes correspond to structural and functional brain alterations. A systematic search of PubMed, Web of Science, and Google Scholar was conducted from inception to November 11, 2025, using terms related to MASLD, cognition, and reward. Eligible studies included adult MASLD populations and observational designs assessing cognitive and/or reward outcomes. Studies involving neuropsychiatric or neurological disorders or medications known to affect cognition were excluded. Fourteen studies (eight cross-sectional, four cohort or case–control, and two Mendelian randomization) found MASLD significantly associated with poorer attention, executive function and memory, often proportional to disease severity. Neuroimaging studies reported significant reductions in cortical thickness, hippocampal and white matter volume, increased white matter hyperintensities, and cerebrovascular dysfunction (p < 0.05), most pronounced in executive and visuospatial regions. Limited evidence suggested alterations in small-to-moderate circuits, including nucleus accumbens dysfunction and reduced hippocampal–orbitofrontal connectivity. MASLD is associated with cognitive impairment, reward-related neural systems, and structural and cerebrovascular brain alterations. These findings reinforce its characterization as a multisystem condition affecting brain health and neuropsychiatric risk. Longitudinal studies with standardized criteria and confounder adjustment are needed to clarify causal mechanisms.

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Cite

BibTeXRIS
BibTeX
@article{mollin2026metabolic,
  title = {{Metabolic dysfunction-associated steatotic liver disease and neurocognitive and reward circuit dysfunction: implications for mental disorders}},
  author = {Nina Sachi Mollin and Gia Han Le and Christine E. Dri and Elim Yang and Folkert van Bruggen and Kangguang Lin and Stavroula Bargiota and Heidi K.Y. Lo and Roger Ho and Taeho Greg Rhee and Bing Cao and Angela T.H. Kwan and Roger S. McIntyre},
  journal = {CNS Spectrums},
  year = {2026},
  month = may,
  doi = {10.1017/s1092852926100984},
  url = {https://doi.org/10.1017/s1092852926100984},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Metabolic dysfunction-associated steatotic liver disease and neurocognitive and reward circuit dysfunction: implications for mental disorders
AU  - Nina Sachi Mollin
AU  - Gia Han Le
AU  - Christine E. Dri
AU  - Elim Yang
AU  - Folkert van Bruggen
AU  - Kangguang Lin
AU  - Stavroula Bargiota
AU  - Heidi K.Y. Lo
AU  - Roger Ho
AU  - Taeho Greg Rhee
AU  - Bing Cao
AU  - Angela T.H. Kwan
AU  - Roger S. McIntyre
PY  - 2026
DA  - 2026/05/26
JO  - CNS Spectrums
DO  - 10.1017/s1092852926100984
UR  - https://doi.org/10.1017/s1092852926100984
AB  - Metabolic dysfunction-associated steatotic liver disease (MASLD) (formerly known as nonalcoholic fatty liver disease) is the most prevalent liver disease globally. Emerging evidence suggests MASLD-related metabolic and inflammatory processes may disrupt frontostriatal–limbic circuits, contributing to alterations in cognitive and reward-related brain function. This systematic review aimed to examine whether MASLD is associated with changes in cognitive functioning and reward-related processes, and whether these changes correspond to structural and functional brain alterations. A systematic search of PubMed, Web of Science, and Google Scholar was conducted from inception to November 11, 2025, using terms related to MASLD, cognition, and reward. Eligible studies included adult MASLD populations and observational designs assessing cognitive and/or reward outcomes. Studies involving neuropsychiatric or neurological disorders or medications known to affect cognition were excluded. Fourteen studies (eight cross-sectional, four cohort or case–control, and two Mendelian randomization) found MASLD significantly associated with poorer attention, executive function and memory, often proportional to disease severity. Neuroimaging studies reported significant reductions in cortical thickness, hippocampal and white matter volume, increased white matter hyperintensities, and cerebrovascular dysfunction (p < 0.05), most pronounced in executive and visuospatial regions. Limited evidence suggested alterations in small-to-moderate circuits, including nucleus accumbens dysfunction and reduced hippocampal–orbitofrontal connectivity. MASLD is associated with cognitive impairment, reward-related neural systems, and structural and cerebrovascular brain alterations. These findings reinforce its characterization as a multisystem condition affecting brain health and neuropsychiatric risk. Longitudinal studies with standardized criteria and confounder adjustment are needed to clarify causal mechanisms.
SN  - 1092-8529
SN  - 2165-6509
ER  -