Table A1.
Summary of structural neuroimaging studies of hallucinating patients with LBD. Only main results related to VH are reported.
| Study | Sample | Age 1 | Disease Duration (years) 1 | VH | MMSE 1 | H&Y | Neuroimaging Methods—VH | Main Results: Neuroimaging and VH |
|---|---|---|---|---|---|---|---|---|
| Blanc et al. (2016) [26] | 28 pro-DLB | 67.5 (9.2) | NA | 60.7% DLB patients | 27.6 (2.1) | NA | Whole brain VBM Covariates: age, TIV, sex, group comparison |
Grey matter volume p ≤ 0.005 uncorrected VH < NVH: L cuneus |
| 27 pro-AD | 69.3 (7.8) | 26.9 (1.9) | ||||||
| 33 HC | 72.4 (10.4) | 29.4 (0.9) | ||||||
| Delli Pizzi et al. (2016) [41] | 19 DLB VH | 76.37 (4.35) | 2.95 (0.91) | NPI | 18.00 (4.83) | NA | ROI MRI ROIs: hippocampal substructures; covariates: age, ed., TIV; relationship with NPIhall |
Grey matter volume Correlation with NPIhall: NS |
| 15 AD | 76.47 (7.17) | 3.00 (0.93) | 16.73 (6.31) | |||||
| 19 HC | 76.21 (4.49) | - | 27.58 (0.69) | |||||
| Delli Pizzi et al. (2014) [43] | 18 DLB VH | 75.4 (4.0) 2 | 2.9 (0.6) 2 | NPI | 19.1 (2.6) 3,4 | NA | Cortical thickness Covariates: MMSE, CAF, and UPDRS; correlation with NPIhall (entire cortex and ROI where DLB ≠ AD) |
Cortical thickness p < 0.05 corrected DLB VH < HC: bilat. pericalcarine, LG, cuneus, precuneus, SPG Correlation with NPIhall: R precuneus and SPG |
| 15 AD | 75.6 (7.6) | 3.1 (0.6) | 18.3 (4.1) | |||||
| 14 HC | 75.5 (5.3) | - | 28.1 (1.6) | |||||
| Delli Pizzi et al. (2014) [45] | 15 DLB VH | 76.3 (4.1) 2 | 2.9 (7) 2 | NPI | 17.7 (5.2) 4,5 | NA | DTI ROI Tractography-based subdivision of the thalami; nuisance factors: MMSE, CAF, and UPDRS; correlation with NPIhall |
Grey matter MD DLB VH > HC: thalamic sub-regions project. to PFC and parieto-occipital cortex bilaterally; R thalamic region project. to amygdala; L thalamic region project. to motor cortex Positive association with NPIhall: R thalamus to parietal (VH freq. and sev.) and occipital cortices (VH sev.) |
| 15 AD | 76.1 (4.9) | 3.1 (6) | 16.7 (5.4) | |||||
| 13 HC | 76.0 (4.2) | - | 28.3 (1.5) | |||||
| Franciotti et al. (2015) [16] | 15 sPD VH | 70 (6) 2 | 11.3 (4.3) 6,7 | NPI and semi-structured interview | 24.3 (2.2) 2 | 3.0 (0.5) 7 | Cortical thickness Analysis within DMN cortical regions; nuisance factor: age; group comparison Resting-state fMRI 8 |
Cortical thicknesss sPD VH vs. sPD NVH: NS sPD VH < ePD: L SFS and IPL, bilat. MFG, LPC sPD VH < HC: L SFS, bilat. MFG, LPC, IPL, PCC sPD NVH < HC: R LPC, bilat. IPL, PCC |
| 15 sPD NVH | 68 (11) | 12.0 (4.5) 7 | 24.7 (1.8) | 3.0 (0.6) 7 | ||||
| 15 ePD NVH | 66 (9) | 3.3 (1.8) | 26.2 (1.8) | 2.1 (0.4) | ||||
| 15 MSA | 67 (5) | 3.9 (1.8) | 25.2 (1.7) | 3.2 (0.8) | ||||
| 15 HC | 69 (6) | - | 28.7 (0.7) | - | ||||
| Gama et al. (2014) [35] | 11 PD VH | 70.6 (9.1) 2 | 7.4 (6.1) 2 | Based on definition of VH | 19.3 (3.7) 9 | From stage I to stage IV | ROI VBM ROIs (SVC): temporal and frontal regions; group comparisons |
Grey matter volume p < 0.05 corrected VH < HC: L opercula and SFG NVH < HC: L SFG |
| 28 PD NVH | 65.7 (7.8) | 6.5 (5.0) | 25.6 (4.3) | |||||
| 10 HC | 68.1 (7.0) | - | 25.6 (4.3) | |||||
| Goldman et al. (2014) [27] | 25 PD VH | 74.8 (6.0) 2 | 13.1 (4.6) 2 | MDS-UPDRS | 23.9 (5.4) 2 | 3 (2-5) 2,10 | Whole brain VBM Covariate: TIV; group comparison; association between regions where VH < NVH and VH sev. |
Grey matter volume p < 0.01 uncorrected VH < NVH: bilat. occipital, occipito-temporal, and parietal regions Correlation with VH sev.: parietal, occipital, and occipito-temporal regions |
| 25 PD NVH | 75.4 (6.1) | 10.8 (4.4) | 25.1 (4.4) | 3 (2-5) 10 | ||||
| Ibarretxe-Bilbao et al. (2010) [34] | 12 PD VH | 73.3 (5.9) 2 | 12.1 (5.7) 2 | Structured interview; NPI | 26.9 (1.9) 4,9,11 | 3.1 (1.1) 9 | Whole brain VBM Covariate: MMSE; comparison between baseline and follow-up in each group; correlations between atrophy progression and cognitive decline in PD VH |
Grey matter loss form baseline to follow-up p < 0.05 corrected VH: bilat. parietal cortex, insula, STG, ITG, SFG, IFG, thalamus and limbic areas, L dorsal PCC NVH: R frontal areas and cerebellum Correlations with grey matter loss in PD VH: learning with L hippocampus, delayed recall with L prefrontal cortex, semantic fluency with L thalamus, language comprehension with L amygdala |
| 14 PD VH | 71.1 (5.7) | 11.9 (4.3) | 29.3 (1.6) | 2.3 (0.5) | ||||
| 12 HC | 70.7 (7.2) | - | 29.5 (2.6) | - | ||||
| Ibarretxe-Bilbao et al. (2008) [32] | 16 PD VH | 73.5 (5.1) 2 | 12.9 (5.9) 2 | Structured interview | 26.0 (2.1) 4,9 | 3.2 (1.1) | ROI VBM ROI: hippocampus; group comparison; correlation analysis with cognitive measures |
Grey matter density p < 0.05 corrected VH vs. NVH and NVH vs. HC: NS VH < HC: bilat. anterior hippocampus Correlation with grey matter loss in anterior hippocampus bilaterally: learning scores in patients with PD VH, but not PD NVH and PDD |
| 19 PD NVH | 72.5 (5.8) | 10.9 (4.2) | 28.2 (1.7) | 2.5 (0.7) | ||||
| 9 PDD | 69.8 (9.5) | 13.1 (5.4) | 15.7 (5.4) | 3.8 (1.0) 12 | ||||
| 56 HC | 73 (6.7) | - | 28.7 (3.1) | - | ||||
| Iizuka and Kameyama (2016) [18] | 24 DLB | 73 (68, 79) 13 | 2.8 (1.8, 3.2) 13 | NPI | 23 (20.5, 24) 13 | NA | ROI MRI ROI: medial temporal lobe, correlation analysis PET 8 |
Negative correlation with NPIhall in DLB: MTL atrophy |
| 24 AD | 74 (69, 81) 13 | 2.3 (1.6, 2.6) 13 | 23 (21, 24.5) 13 | |||||
| Janzen et al. (2012) [28] | 13 PD VH | 66.0 (6.9) 2 | 11.5 (5.2) | SCOPA-PC | 28.0 (1.7) | 2.5 (0.3) 16 | ROI VBM ROI: thalamus and pedunculopontine nucleus; covariates: age, TIV; group comparisons Whole brain VBM Post-hoc analysis; group comparisons |
Grey matter volume ROI VBM p < 0.05 corrected PD VH < PD NVH: bilat. PPN PD/PDD VH < PD NVH: bilat. PPN and thalamus Whole brain VBM p < 0.001 uncorrected PD/PDD VH < PD NVH: PPN and thalamus DLB/PDD VH < PD VH: R MFC |
| 13 PDD VH | 67.7 (7.1) | 10.9 (5.5) | 21.2 (2.7) 12,14 | 3.5 (1.0) 12,14 | ||||
| 16 PD NVH | 64.3 (8.0) | 3.1 (3.6) | 28.9 (1.6) 15 | 2.1 (0.5) | ||||
| 11 DLB | 62.6 (6.5) | 4.6 (4.5) | 24.5 (1.4) | NA | ||||
| Kantarci et al. (2010) [46] | 30 DLB | 71 (55, 85) 10 | NA | VH definition; 64% of DLB | 27 (14, 34) 10,17 | NA | DTI ROI ROI: cortical GM regions and white matter tracts; group comparisons |
Mean diffusivity VH > NVH: ILF |
| 30 AD | 74 (48, 89) 10 | 24 (5, 33) 10,17 | ||||||
| 60 HC | 73 (54, 86) 10 | 36 (28, 38) 10,17 | ||||||
| Kantarci et al. (2012) [19] | 21 DLB | 73 (60, 87) 10 | NA | Freq. of VH: 4 point scale90% of DLB | 22 (6, 29) 10 | NA | ROI MRI Association between freq. of VH and hippocampal volumes in DLB PET 8 |
Hippocampal volume Association with VH freq.: NS |
| 21 AD | 77 (58, 92) 10 | 21 (6, 28) 10 | ||||||
| 42 HC | 74 (59, 87) 10 | 29 (27, 30) 10 | ||||||
| Lee et al. (2016) [20] | 10 PD VH | 69.2 (5.2) 2 | 7.2 (3.7) 2 | Semi-structured interview | 27.7 (1.6) 2 | 2.2 (0.5) 2 | DTI ROI ROI: optic nerve, optic radiation bilaterally; group comparisons ROI MRI ROIs: optic chiasm area; LGN volume; V1 volume; each volume divided by TIV; group comparison |
White matter integrity p < 0.016 corrected VH < HC: FA: L optic nerve FA NVH < HC: MD: bilat. optic nerve VH > NVH and HC: MD: L optic radiation VH > NVH: axial diffusivity: R optic nerve VH > HC: RD: L optic radiation Grey matter volume VH < NVH: volume: L LGN VH < HC: volume: bilat. LGN |
| 14 PD NVH | 66.1 (6.1) | 7.3 (3.7) | 28.4 (1.4) | 2.1 (0.5) | ||||
| 15 HC | 68.5 (6.6) | - | NA | - | ||||
| Lee et al. (2017) [21] | 10 PD VH | 69.4 (5.3) 2 | 7.2 (3.7) 2 | Based on consensus criteria during clinical follow-up | 27.6 (1.8) | 2.2 (0.3) 12,14,16 | Whole brain VBM Covariates: age, gender, TIV; group comparisons; TBSS DTI Group comparisons; covariates: age, gender |
Grey matter volume p < 0.001 uncorrected PD VH < PD NVH: R IPL, and SG White matter p < 0.05 corrected PD VH vs. PD NVH: FA: NS PD VH < HC: FA: fronto-temporo-parietal and brainstem regions bilaterally PD NVH < HC: FA: fronto-temporal-parietal areas, midbrain and pons bilaterally PD VH > HC: MD: L temporo-parietal, and lateral geniculate areas |
| 21 PD NVH | 66.2 (6.8) | 7.0 (4.2) | 28.2 (1.4) | 1.8 (0.5) | ||||
| 17 PDD VH | 71.1 (5.0) | 6.2 (3.0) | 20.4 (3.7) 12,14 | 2.8 (0.8) | ||||
| 30 HC | 68.6 (6.0) | - | NA | - | ||||
| Meppelink et al. (2011) [24] | 11 PD VH | NA 2 | 8.0 (4.7) | NPI | NA 2 | NA | Whole brain VBM Group comparisons; covariates: total grey matter ROI MRI ROI: L FG |
Grey matter volume Whole brain VBM p < 0.05 cluster-level corrected VH vs. NVH: NS VH < HC: L temporal areas, parietal, occipital, frontal regions bilaterally NVH < HC: L occipital, temporal regions, frontal and parietal regions bilaterally ROI: FG: NS |
| 13 PD NVH | NA | 7.9 (2.4) | NA | |||||
| 14 HC | NA | - | NA | |||||
| Pagonabarraga et al. (2014) [29] | 17 PD mVH | 64.1 (9) 2 | 9.8 (7) 2 | MDS-UPDRS | 87.2 (13) 2, 18 | 1.9 (0.3) 2 | Whole brain VBM Covariates: age, gender, global grey matter volume; group comparisons; cluster threshold of 207 voxels determined through 1000 Monte Carlo simulations |
Grey matter volume p < 0.001 uncorrected mVH < NVH: R vermis, and precuneus mVH > NVH: cerebellum, L IFC |
| 29 PD NVH | 66.3 (8) | 7.3 (4) | 90.3 (13) | 1.9 (0.4) | ||||
| 16 HC | 66.8 (8) | - | 91.6 (11) | - | ||||
| Pereira et al. (2013) [42] | 6 PD VH | 73.7 (5.4) 2 | 12.9 (5.7) 2 | NPI | 26.1 (2) 4,9 | 3.1 (1) 2 | ROI MRI ROI: hippocampal subfields; correlations with cognitive measures |
Grey matter volume VH vs. NVH: NS VH and NVH < HC: CA2-3, CA4-DG VH < HC: subiculum, whole hippocampus |
| 6 PD NVH | 73.8 (6.8) | 12.8 (6.3) | 27.9 (1.4) | 2.9 (0.9) | ||||
| 6 HC | 73.6 (6.7) | - | 27.9 (2.1) | - | ||||
| Ramirez-Ruiz et al. (2007) [30] | 18 PD VH | PD matched with HC | 12.6 (5.6) 2 | NPI and structured questionnaire | 27.0 (2.1) 4,9 | 3.2 (1.0) 9 | Whole brain VBM Covariates: TIV, MMSE, Hamilton, and H&Y scores; group comparison |
Grey matter volume p < 0.05 cluster-level corrected VH < NVH: L LG and bilat. SPL |
| 20 PD NVH | 10.6 (4.3) | 29.1 (1.4) | 2.5 (0.7) | |||||
| 21 HC | - | 29.4 (2.3) | - | |||||
| Sanchez-Castaneda et al. (2010) [33] | 6 DLB VH | 70.17 (12.4) 2 | 32.8 (17.7) 19 | NPI and Burnes Questionnaire | 17.5 (5) 2 | 2.6 (0.5) 2 | ROI VBM ROI: frontal, occipital, parietal, and temporal areas; covariates: TIV, disease duration, duration of dementia; group comparison; correlation analysis |
Grey matter volume p < 0.05 corrected DLB VH < DLB NVH: R IFG PDD VH < PDD NVH: L OFC Correlations with VH sev. p < 0.05 corrected DLB: R IFG (r = 0.89), L precuneus (r = 0.95) PDD: NS |
| 6 DLB NVH | 70.6 (7.1) | 30 (11.8) 19 | 21.2 (8.1) | 3 (0.7) | ||||
| 8 PDD VH | 75.3 (4.9) | 40.5 (16.8) 19, 20 | 21.5 (3.5) | 2.8 (0.6) | ||||
| 7 PDD NVH | 70.6 (7.1) | 66 (24.8) 19 | 23.5 (4) | 2.6 (1) | ||||
| Shin et al. (2012) [25] | 46 PD VH | 71.3 (5.9) 2 | 3.3 (3.0) 2 | NPI | 25.2 (3.0) 2 | NA | Whole brain VBM Group comparison; covariates: age, sex, PD duration, intracerebral volume, MMSE score ROI MRI Manually delineation of the ROI; group comparisons |
Grey matter volume VBM VH < NVH p < 0.001 uncorrected R IFC, L temporal, and thalamic areas VH < HC p < 0.05 corrected Parahippocampal area, insular cortex ROI VH < NVH: SI volume Correlations with SI volume: verbal memory immediate, and delayed recall, semantic fluency, go/no-go tests |
| 64 PD NVH | 70.7 (5.7) | 2.8 (3.0) | 25.7 (2.9) | |||||
| Watanabe et al. (2013) [31] | 13 PD VH | 66.6 (5.5) 2 | 10.0 (5.2) 2 | UPDRS I | 27.9 (1.9) 2 | 2.9 (0.6) 2 | Whole brain VBM Covariates: TIV, age, sex; group comparison |
Grey matter volume VH < NVH p < 0.005 uncorrected Bilat. PFC, PFC, L ventral cingulate cortex, primary visual cortex, PCC, occipito-temporal regions, R parietal, temporal, occipital regions |
| 13 PD NVH | 63.6 (10.7) | 10.0 (4.0) | 29.0 (1.5) | 2.4 (0.8) | ||||
| 22 HC | 63.4 (6.1) | - | 29.8 (0.4) | - | ||||
| Yao et al. (2016) [22] | 12 PD VH | 70 (64, 72.75) 2, 13 | 9.1 (3.5) 2 | PPRS | 28.5 (24, 29.75) 2,13 | 3.1 (0.7) 2 | ROI MRI Volume, and shape of the hippocampus; covariates: age, MMSE, intracranial volume; group comparison ROI DTI MD of the hippocampus; voxel-based MD of the hippocampus; covariates: age, MMSE; group comparison Resting-state fMRI 8 |
Hippocampal volume and shape: NS VH > NVH and HC: MD: R hippocampus; voxel-based MD (p < 0.05 corrected): R posterior hippocampal regions |
| 15 PD NVH | 66 (62, 72) 2 | 7.1 (5.1) | 29 (28, 30) 13 | 2.9 (0.7) | ||||
| 14 HC | 63 (62, 68.75) 2 | - | 29 (28, 29.25) 13 | - | ||||
| Yao et al. (2014) [17] | 12 PD VH | 67.6 (7.4) 2 | 10.0 (3.5) 2 | PPRS | 27.6 (2.4) 2 | 3.2 (0.7) 2 | Cortical thickness Covariates: age, MMSE score and levodopa-equivalent dosage; group comparison Resting-state fMRI 8 |
Cortical thickness p < 0.05 cluster-level corrected No differences between groups |
| 12 PD NVH | 63.4 (7.4) | 8.4 (5.1) | 28.5 (1.7) | 2.8 (0.9) | ||||
| 14 HC | 64.1 (4.0) | - | 29.1 (0.7) | - |
1 Mean (SD); 2 no significant differences between groups; 3 no significant differences with AD; 4 VH ≠ HC; 5 no differences between DLB and AD; 6 no differences between sPD VH and sPD NVH; 7 sPD VH and NVH ≠ ePD; 8 functional neuroimaging is reported in Table A2; 9 VH ≠ NVH; 10 median (range); 11 MMSE: VH 6.5 point decline after 2 years follow-up (higher percentage of loss compared to NVH); 12 PDD ≠ PD NVH; 13 median (interquartile range); 14 PDD ≠ PD VH; 15 PD NVH ≠ DLB; 16 PD VH ≠ PD NVH; 17 Short test of Mental Status; 18 Parkinson’s disease-Cognitive Rating Scale; 19 months; 20 PDD VH ≠ DLB VH, DLB NVH, PDD VH. AD: Alzheimer’s disease; bilat.: bilateral; CAF: Clinician Assessment of Fluctuations; DLB: dementia with Lewy bodies; ed.: education; ePD: early PD; FA: fractional anisotropy ; FAB: Frontal Assessment Battery; FG: fusiform gyrus; freq.: frequency; H&Y: Hoehn and Yahr stage; HC: healthy controls; IFC: inferior frontal cortex; IFG: inferior frontal gyrus; IPL: inferior parietal lobule; ITG: inferior temporal gyrus; LG: lingual gyrus; LGN: lateral geniculate nucleus; LPC: lateral parietal cortex; MD: mean diffusivity; MDS: Movement Disorders Society; MF: middle frontal gyrus; MFC: middle frontal cortex; MMSE: Mini-Mental State Examination; MRI: magnetic resonance imaging; MSA: multiple system atrophy; NA: not available; NPI: Neuropsychiatric Inventory; NPIhall: NPI hallucination score; NS: not significant; NVH: no VH; OFC: orbitofrontal cortex; PCC: posterior cingulate cortex; PD: Parkinson’s disease; PDD: Parkinson’s disease dementia; PFC: prefrontal cortex; PPN: pedunculopontine nucleus; PPRS: Parkinson psychosis rating scale; pro-AD: prodromal AD; pro-DLB: prodromal DLB; project.: projecting; RD: radial diffusivity; ROI: region of interest; SCOPA-PC: Scales for Outcome in Parkinson’s disease Psychiatric Complications; sev.:severity; SFG: superior frontal gyrus; SFS: superior frontal sulcus; SG: supramarginal gyrus; SI: Substantia innominate; sPD: severe PD; SPG: superior parietal gyrus; SPL: superior parietal lobe; STG: superior temporal gyrus; UPDRS: Unified Parkinson’s Disease Rating Scale; VBM: voxel-based morphometry; VH: visual hallucinations.