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Mapping brain structural differences and neuroreceptor correlates in Parkinson’s disease visual hallucinations
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Abstract
Parkinson’s psychosis (PDP) describes a spectrum of symptoms that may arise in Parkinson’s disease (PD) including visual hallucinations (VH). Imaging studies investigating the neural correlates of PDP have been inconsistent in their findings, due to differences in study design and limitations of scale. Here we use empirical Bayes harmonisation to pool together structural imaging data from multiple research groups into a large-scale mega-analysis, allowing us to identify cortical regions and networks involved in VH and their relation to receptor binding. Differences of morphometrics analysed show a wider cortical involvement underlying VH than previously recognised, including primary visual cortex and surrounding regions, and the hippocampus, independent of its role in cognitive decline. Structural covariance analyses point to the involvement of the attentional control networks in PD-VH, while associations with receptor density maps suggest neurotransmitter loss may be linked to the cortical changes.
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Morphological and functional alterations differentiate patients with PD with VH from those without VH.
“Although morphological5–7 and functional7–9 alterations differentiate patients with PD with VH (PD-VH) from those without VH”
From Deviations in effective connectivity explain different hallucination subtypes in Parkinson's disease psychosis (2026) · cites this paper as [5]
The Results report decreased cortical thickness and surface area in patients with PD and visual hallucinations compared with those without, supporting the morphological part of the claim. The Discussion suggests possible functional pathology but says it needs further exploration with functional connectivity; it does not establish functional differences between the groups. (LLM, conf=0.86)
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Cerebellar involvement in hallucinations may transcend clinical conditions and perceptual modalities
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The neuropsychiatry of Parkinson's disease: advances and challenges
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Self-citationParkinson disease psychosis: from phenomenology to neurobiological mechanisms
Pagonabarraga, J., Bejr-Kasem, H., Martinez-Horta, S., & Kulisevsky, J. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-023-00918-8 · Cited by 69
“…changes are attributable to synaptic loss secondary to diminished neurotransmitter input, as dopaminergic, serotonergic and cholinergic systems are well known to be involved in PD, and a correlation between preservation of neurochemical function and cortical thickness has been described 87 .”
Imaging the Limbic System in Parkinson’s Disease—A Review of Limbic Pathology and Clinical Symptoms
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Visual Dysfunction in Parkinson’s Disease
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Neuropathological correlates of neuropsychiatric symptoms in dementia
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Self-citationLawn, T., Dipasquale, O., Vamvakas, A., Tsougos, I., Mehta, M. A., & Howard, M. A. (2022) · Psychopharmacology · doi:10.1007/s00213-022-06117-5 · Cited by 39
Self-citationGenomic loci influence patterns of structural covariance in the human brain
Wen, J., Nasrallah, I. M., Abdulkadir, A., Satterthwaite, T. D., Yang, Z., Erus, G., Robert‐Fitzgerald, T., Singh, A., Sotiras, A., Boquet-Pujadas, A., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2300842120 · Cited by 33
“…within a relatively limited scope, such as within relatively small samples, over a relatively narrow age window [e.g., adolescence (2)], within a single disease [e.g., Parkinson’s disease (6)], or within datasets lacking sufficient diversity in cohort characteristics or MRI scanner protocols.”
Visual hallucinations in Parkinson’s disease: spotlight on central cholinergic dysfunction
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Self-citationThe structural changes of gray matter in Parkinson disease patients with mild cognitive impairments
Li, L., Ji, B., Zhao, T., Cui, X., Chen, J., & Wang, Z. (2022) · PLoS ONE · doi:10.1371/journal.pone.0269787 · Cited by 29
Khan, A. F., & Iturria‐Medina, Y. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03073-w · Cited by 31
“…densities and disease-associated imaging features, such as atrophy patterns in schizophrenia patients with dyskinesia or parkinsonism [208], cortical thinning in PD patients with and without visual hallucinations [209], and white matter tract alterations in major psychiatric disorders (MPDs) [210].”
BackgroundCatd: unified representation learning for eeg-to-fmri cross-modal generation
Yao, W., Lyu, Z., Mahmud, M., Zhong, N., Lei, B., & Wang, S. (2025) · IEEE Transactions on Medical Imaging · doi:10.1109/tmi.2025.3550206 · Cited by 24
“…gyrus and the lateral occipito-temporal gyrus [52], which, in patients with Parkinson’s disease, shows significant structural changes [53], and in patients with PD accompanied by visual hallucinations, the atrophy of these three brain regions correlates with the severity of visual…”
Structural and Functional Imaging Correlates of Visual Hallucinations in Parkinson’s Disease
Bhome, R., Thomas, G. E. C., Zarkali, A., & Weil, R. (2023) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-023-01267-1 · Cited by 10
Self-citationPisani, S., Gunasekera, B., Lu, Y., Vignando, M., Ffytche, D. H., Aarsland, D., Chaudhuri, К. R., Ballard, C. G., Lee, J., Kim, Y. K., et al. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105081 · Cited by 14
Self-citationMRI Assessment of Intrinsic Neural Timescale and Gray Matter Volume in Parkinson's Disease
Wei, Y., Zhang, C., Peng, Y., Chen, C., Han, S., Wang, W., Zhang, Y., Lu, H., & Cheng, J. (2023) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.28864 · Cited by 13
Visual mismatch negativity in Parkinson's psychosis and potential for testing treatment mechanisms
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“21 Two studies have directly tested striatal and extra-striatal serotonin markers in PDP. Direct measurement of 5-HT2 A receptor availability has produced mixed findings with two studies showing an increase in binding in the ventral visual pathway, and one showing a decrease in binding.”
BackgroundResultInfluentialSelf-citationDeng, J.-H., Zhang, H., Liu, X.-L., Deng, H.-Z., & Lin, F. (2022) · World Journal of Psychiatry · doi:10.5498/wjp.v12.i12.1356 · Cited by 5
Knolle, F., Arumugham, S. S., Barker, R. A., Chee, M. W. L., Justicia, A., Kamble, N. L., Lee, J., Liu, S., Lenka, A., Lewis, S. J. G., et al. (2023) · npj Parkinson s Disease · doi:10.1038/s41531-023-00522-z · Cited by 5
Self-citationModafinil alters the functional connectivity of distinct thalamic nuclei with the neocortex
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Miyata, M., Kakeda, S., Yoneda, T., Ide, S., Okada, K., Adachi, H., & Korogi, Y. (2022) · Scientific Reports · doi:10.1038/s41598-022-21847-4 · Cited by 4
Pisani, S., Gunasekera, B., Lu, Y., Vignando, M., Ffytche, D. H., Aarsland, D., Chaudhuri, К. R., Ballard, C. G., Lee, J., Kim, Y. K., et al. (2024) · Brain Communications · doi:10.1093/braincomms/fcae358 · Cited by 3
“As a number of recent reviews on the structural correlates of PDP exist 17,19 including one from our group, 16 here, we primarily focused on summarizing evidence from studies using other neuroimaging modalities.”
BackgroundResultSelf-citationIgnatavicius, A., Churchill, L., Anderson, J., Konuri, A., O’Callaghan, C., Lewis, S. J. G., & Matar, E. (2025) · Movement Disorders · doi:10.1002/mds.70011 · Cited by 3
“29 The amygdala shares connections with the regions within the ventral visual stream, as well as exogenous and endogenous attentional networks, suggesting it acts as a convergence point for integrating top-down and bottom-up information.”
Self-citationVisual Hallucinations in Serotonergic Psychedelics and Lewy Body Diseases
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“Vignando et al. 107 found that 5-HT 2A R /5-HT 1A R receptor distributions correlate with hallucination-specific cortical degeneration patterns, distinct from those linked to dopamine.”
Self-citationPitfalls of mapping functional and molecular human brain imaging data from separate cohortsPreprint
Fisher, P. M., Larsen, K., Plavén‐Sigray, P., Knudsen, G. M., & Ozenne, B. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.22.650037 · Cited by 3
Ma, Y., Liu, T., Yang, G., Wang, K., Lai, R., Han, Z., Zhang, J., Zhang, K., Wang, X., Funahashi, S., et al. (2026) · NeuroImage · doi:10.1016/j.neuroimage.2026.122001 · Cited by 2
Wu, J., Jin, X., Xie, W., Liu, L., Wang, F., Zhu, L., Shen, Y., & Qiu, L. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1480234 · Cited by 2
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Electrophysiological Signatures of Visual Sensations Elicited by Direct Electrical Stimulation
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“Regions exhibiting flatter spectral slopes during visual sensations showed remarkable overlap with structural abnormalities identified in Parkinson’s disease patients with visual hallucinations [47].”
Sui, H., Mo, Z., Shi, F., Zhou, Q., Yu, D., Wang, J., & Liu, L. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1602245 · Cited by 1
Stampacchia, S., Bernasconi, F., Ville, D. V. D., Amico, E., Kohoutová, L., Taylor, J., Thomas, A. J., Pagonabarraga, J., Kulisevsky, J., & Blanke, O. (2026) · Nature Mental Health · doi:10.1038/s44220-026-00657-x · Cited by 1
“Previous studies have reported alterations in cholinergic, sero-tonergic, dopaminergic and GABAergic systems in patients with PD and hallucinations 48–50 .”
Self-citationData-driven trajectories of atrophy explain clinical heterogeneity across Lewy body diseases
Konuri, A., Leal, G. C., Zebarjadi, N., Habich, A., Castellanos-Perilla, N., González, M. C., Taylor, J., Firbank, M., Alcolea, D. A., Bejanin, A., et al. (2026) · EBioMedicine · doi:10.1016/j.ebiom.2026.106400 · Cited by 2
“31 However, recent structural and functional imaging evidence implicates the amygdala as a central convergence hub, integrating visual and limbic processes, 32,33 with voxel-level mapping highlighting it as a dominant locus of visual dysfunction relative to adjacent limbic structures.”
Self-citationMega-analysis of brain structural covariance, genetics, and clinical phenotypesPreprint
Wen, J., Nasrallah, I. M., Abdulkadir, A., Satterthwaite, T. D., Erus, G., Robert‐Fitzgerald, T., Singh, A., Sotiras, A., Boquet-Pujadas, A., Yang, Z., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-1503113/v1 · Cited by 1
Vignando, M., Ffytche, D., Mazibuko, N., Palma, G., Bhat, A., Montagnese, M., Dave, S., Tai, Y. F., Batzu, L., Leta, V., et al. (2026) · Nature Mental Health · doi:10.1038/s44220-026-00669-7
Self-citationAbnormal intrinsic neural timescale and reduced grey matter volume in Parkinson’s diseasePreprint
Wei, Y., Zhang, C., Peng, Y., Chen, C., Han, S., Wang, W., Zhang, Y., Lu, H., & Cheng, J. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.17.508074
Neural substrates in Parkinson’s Disease psychosis: A systematic reviewPreprint
Pisani, S., Gunasekera, B., Lu, Y., Vignando, M., Ffytche, D. H., Aarsland, D., Chaudhuri, К. R., Ballard, C. G., Lee, J., Kim, Y. K., et al. (2022) · medRxiv · doi:10.1101/2022.12.23.22283889
Self-citationLi, Q., Huang, Z., Wang, J., Liang, M., Jia, C., Yuan, J., & Cui, R. (2025) · Brain Sciences · doi:10.3390/brainsci15121264
“In contrast, AD patients rarely experience visual hallucinations, and PD patients may develop simple visual hallucinations (e.g., shadows, distorted objects) only in late stages (more than 10 years after motor symptom onset) [37].”
Parkinson's psychosis structural mega-analysis
Mehta, M. A., Vignando, M., & Ffytche, D. H. (2020) · Open Science Framework · doi:10.17605/osf.io/nzatk
Self-citationPisani, S., Váša, F., Velayudhan, L., & Bhattacharyya, S. (2026) · Movement Disorders · doi:10.1002/mds.70222
“…extent of cortical and subcortical gray matter volume loss that has been reported in PD patients who develop psychosis compared to those who do not 8,28 and that was also evident from our meta-analytic examination 7 may be linked to local expression of the CB1 receptor, consistent with positron…”
Age differences in episodic memory for restructured novel objects: The effect of schema deviations
Xu, H.-Z., Huan, S.-Y., Chen, J., Wang, J., & Yu, J. (2026) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2026.108155
Mega-Analysis of Structural Brain Imaging in Functional Neurological Disorder
Butler, M., Vignando, M., Allendorfer, J. B., Hassa, T., Horovitz, S. G., Jansen, J. F. A., Jungilligens, J., Kerr, W. T., Marapin, R. S., Premi, E., et al. (2026) · Biological Psychiatry · doi:10.1016/j.biopsych.2026.06.031 · Cited by 1
“This method has been previously used successfully in studies of cortical thickness, cortical surface area, and subcortical volumes (37,43) (see Supplemental Note S1 for more details).”
InfluentialSelf-citationMonopoli, G., Tomaiuolo, F., Sestieri, C., Punzi, M., Marino, S., Gambi, F., Perrucci, M. G., Ferretti, A., Sensi, S. L., & Pizzi, S. D. (2026) · Brain Communications · doi:10.1093/braincomms/fcag357
“4,13,27,28 In contrast, the occurrence of mVHs in untreated PD patients suggests that these experiences cannot be solely attributed to dopaminergic therapy.”
Metadata
- Authors
- Vignando, M., ffytche, D., Lewis, S. J. G., Lee, P. H., Chung, S. J., Weil, R. S., Hu, M. T., Mackay, C. E., Griffanti, L., Pins, D., Dujardin, K., Jardri, R., Taylor, J.-P., Firbank, M., McAlonan, G., Mak, H. K. F., Ho, S. L., & Mehta, M. A.
- Affiliations
- King's College London (GB)
- The University of Sydney (AU)
- Yonsei University (KR)
- University College London (GB)
- University of Oxford (GB)
- Inserm (FR)
- Newcastle University (GB)
- University of Hong Kong (HK)
- Corresponding author
- Vignando, Miriam
- ORCID
- Venue
- Nature Communications
- Published
- 2022-01-26
- Volume
- 13
- Issue
- 1
- Pages
- 519-519
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8791961
- OpenAlex
- W4210783444
- Cited by
- 42
- References
- 98
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 6 · 2023: 6 · 2022: 11
- FWCI
- 4.00
- Type
- journal article
- Language
- en
- Update notices
- correction (2022-02-15)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- medRxiv (acceptedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, cc-by)
- HAL (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- LillOA (Université de Lille (University Of Lille)) (submittedVersion, other-oa)
- LillOA (Université de Lille (University Of Lille)) (submittedVersion, cc-by)
- Funders
- RCUK | Medical Research Council (MR/0059311)
- The grant has been awarded to Prof. Mitul Mehta and Dr. Vignando has been supported with this grant.
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Hallucinations in medical conditions
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Parkinson's disease psychosis, visual hallucinations, Parkinson's disease, cortical morphometry, structural covariance, primary visual cortex, hippocampus, neuroreceptor binding, dopamine receptor density, serotonin receptor density, mega-analysis
- MeSH terms
- Aged, Bayes Theorem, Brain, Brain Mapping, Cerebral Cortex, Female, Hallucinations, Hippocampus, Humans, Male, Middle Aged, Parkinson Disease, Sensory Receptor Cells
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