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Neurophysiological signature(s) of visual hallucinations across neurological and perceptualDauwan, Meenakshi

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CHAPTER

Neuroimage Clinical, 2019; 13;22:101752

1 University of Groningen, University Medical Center Groningen, The Netherlands2 Amsterdam UMC, Vrije Universiteit, Department of Clinical Neurophysiology and MEG Center, The Netherlands 3 Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands 4 Department of Neurology, St. Antonius Ziekenhuis, Utrecht, The Netherlands5 Department of Neurology, Diakonessenhuis Utrecht, The Netherlands6 Department of Biological and Medical Psychology, University of Bergen, Norway

Meenakshi Dauwan1,2,3

J.I. Hoff4

E.M. Vriens5

A. Hillebrand2

C.J. Stam2*I.E. Sommer1,6*

* These authors are joint senior authors

6Aberrant resting-state

oscillatory brain activity in Parkinson’s disease patients with visual hallucinations:

An MEG source-space study

130

Chapter 6

ABSTRACT

To gain insight into possible underlying mechanism(s) of visual hallucinations (VH) in

Parkinson’s disease (PD), we explored changes in local oscillatory activity in different

frequency bands with source-space magnetoencephalography (MEG). Eyes-closed

resting-state MEG recordings were obtained from 20 PD patients with hallucinations

(Hall+) and 20 PD patients without hallucinations (Hall-), matched for age, gender

and disease severity. The Hall+ group was subdivided into 10 patients with VH only

(unimodal Hall+) and 10 patients with multimodal hallucinations (multimodal Hall+).

Subsequently, neuronal activity at source-level was reconstructed using an atlas-based

beamforming approach resulting in source-space time series for 78 cortical and 12

subcortical regions of interest in the automated anatomical labeling (AAL) atlas. Peak

frequency (PF) and relative power in six frequency bands (delta, theta, alpha1, alpha2,

beta and gamma) were compared between Hall+ and Hall-, unimodal Hall+ and Hall-,

multimodal Hall+ and Hall-, and unimodal Hall+ and multimodal Hall+ patients. PF

and relative power per frequency band did not differ between Hall+ and Hall-, and

multimodal Hall+ and Hall- patients. Compared to the Hall- group, unimodal Hall+

and lower PF (p=.011). Compared to the unimodal Hall+, multimodal Hall+ showed

showed slowing of MEG-based resting-state brain activity with an increase in theta

activity, and a concomitant decrease in beta and gamma activity, which could indicate

central cholinergic dysfunction as underlying mechanism of VH in PD. This signature

was absent in PD patients with multimodal hallucinations.

131

MEG-based resting-state brain activity in PD

1. INTRODUCTION

Visual hallucinations (VH) are the most common type of hallucinations in Parkinson’s

disease (PD) with an overall prevalence of 22% to 38% (Fénelon, 2008; Goetz et al.,

2011; Onofrj and Gilbert, 2018), followed by auditory (AH), olfactory (OH) and tactile

(TH) hallucinations, which are less common with prevalence rates of 3-22% (Fénelon,

2008), 6-16% (Fénelon, 2008; Kulick et al., 2018), and 4-7% (Goetz et al., 2011; Kulick

et al., 2018), respectively. Cognitive impairment in PD is strongly associated with

VH (Fenelon and Alves, 2010; Hepp et al., 2013; Lenka et al., 2017b). In contrast,

multimodal hallucinations in PD are not necessarily associated with a greater risk of

cognitive impairment (R Inzelberg et al., 1998; Katzen et al., 2010). Hallucinations in PD

are associated with higher caregiver burden and form a strong and independent risk

factor for nursing home placement (Aarsland et al., 2000; Fenelon and Alves, 2010).

The majority of research examining the pathophysiology of hallucinations in PD involve

studies on VH. In contrast, nonvisual hallucinations in PD, reported to accompany

VH as a second modality experience (Goetz et al., 2011), remain understudied (Kulick

et al., 2018). As such, dysfunctional activation of frontal (top-down) and posterior

(bottom-up) brain regions have been reported in PD patients with VH (Boecker et

al., 2007; Ffytche et al., 2017; Lenka et al., 2015; Nagano-Saito et al., 2004; Prell, 2018;

Ramírez-Ruiz et al., 2008; Sanchez-Castaneda et al., 2010; Stebbins et al., 2004). In

addition, multiple neurotransmitter systems have been related to hallucinations in

PD: 1) the cholinergic system, 2) the dopaminergic system, and 3) the serotonergic

system (Factor et al., 2017). First, the central cholinergic system is a modulator of the

interaction between feedback or top-down and feedforward or bottom-up processing

(Collerton et al., 2005; Friston, 2005), such that cholinergic dysfunction may increase

the uncertainty in top-down activity resulting in incorrect scene representation, and

thus hallucinations (Collerton et al., 2005; Friston, 2005). Support for this hypothesis

of impaired bottom-up (i.e. reduced activation and metabolism in the visual pathways)

and top-down (i.e. defective attentional) processing has been found in PD patients

with VH and this dysfunctional top-down and bottom-up processing has also been

associated with cognitive decline in PD (Boecker et al., 2007; Dagmar H. Hepp et al.,

6

132

Chapter 6

2017; Matsui et al., 2006; Meppelink et al., 2009; Park et al., 2013; Stebbins et al., 2004).

Second, drug-induced (mostly visual) hallucinations in PD, either or not accompanied

with delusions, have been associated with dopaminergic treatment. Dopamine agonists

have the highest risk of inducing this type of hallucinations, which are independent of

cognitive decline and reverse with adjustment of dopaminergic drug treatment (Factor

et al., 2017; Zahodne and Fernandez, 2008). Third, dysfunction of the serotonin system

has been related to hallucinations in PD. In addition, response to pimavanserin (a

5-HT2A inverse-agonist), a novel antipsychotic for PD with no effect on dopamine

receptors, underscores the role of serotonin in psychosis in PD (Factor et al., 2017;

Kianirad and Simuni, 2017). It remains unclear why some PD patients develop only

VH while others also develop hallucinations in other modalities. One hypothesis is

related to other factors such as dopaminergic medication (Goetz et al., 1998; McAuley

and Gregory, 2012). This is an interesting hypothesis, as it suggests different treatment

options for both subtypes of hallucinations. In this study, we wish to investigate the

underlying mechanisms of hallucinations in PD using magnetoencephalography (MEG).

MEG is a non-invasive technique to measure neuronal activity directly, and study

normal and pathological (oscillatory) brain activity in health and disease (Stam and

van Straaten, 2012). Activation of brain regions is often accompanied with decreases

or increases in signal power in a particular frequency band due to changes in local

synchrony in the underlying neuronal networks (Pfurtscheller and Lopes da Silva, 1999;

local cortical network interactions mainly involve oscillations above 30 Hz (i.e. gamma

band) and mediate feedforward processing, whereas long-range interactions among

distant brain regions are mediated through oscillations below 30 Hz (i.e. theta (4-8

Hz), alpha (8-13 Hz) and beta (13-30 Hz)) and facilitate integrative brain functions and

feedback attentional processing (Bastos et al., 2015; Donner and Siegel, 2011; Siegel

et al., 2012; Uhlhaas and Singer, 2013; von Stein and Sarnthein, 2000). Furthermore,

both alpha and beta oscillations are boosted by cholinergic enhancement (Bauer et al.,

133

MEG-based resting-state brain activity in PD

2012a) and play a role in feedback processes in the context of (visual) attention tasks

Lopes da Silva, 2013). In addition, the modulatory effect of acetylcholine on oscillatory

brain activity is further supported by acetylcholine antagonists that induce a so-called

‘slowing’ of oscillatory brain activity with decrease in alpha and beta activity and

increase in delta and theta activity (Bauer et al., 2012a; Simpraga et al., 2018, 2017).

Therefore, MEG may be of great value to provide an intrinsic temporal view of the

brain in relation to hallucinations.

In the present study, in order to gain insight into the pathophysiological mechanism(s)

patients with unimodal VH (unimodal Hall+) and compared this with PD patients with

multimodal hallucinations (multimodal Hall+) and PD patients without hallucinations

(Hall-). Given the predominant occurrence of VH in PD, in this study, patients were

recruited according to the criterium of presence or absence of hallucinations. After

inclusion, patients with hallucinations were divided into a subgroup with only VH and

a subgroup with multimodal hallucinations (see methods for details).

system has been associated with top-down processing and enhancement of alpha and

decrease in alpha and beta frequencies, and increase in delta and theta frequencies) of

oscillatory brain activity in PD patients who experienced only VH.

2. METHODS

2.1 Study population

Twenty PD patients with hallucinations (Hall+) and 20 without hallucinations (Hall-)

were recruited from the Understanding Hallucinations (UH) study, and included in the

Understanding Hallucinations – MEG (UH-MEG) study at the department of Clinical

Neurophysiology of the VU University Medical Center (VUmc) in Amsterdam, The

Netherlands. UH-MEG is a follow-up study of the UH study, which is an ongoing

multicenter cross-sectional study that investigates phenomenology and underlying brain

6

134

Chapter 6

mechanisms of hallucinations across different neurological, psychiatric and perceptual

³18 years, mentally competent and PD diagnosis determined by the treating neurologist,

(i.e. Hall+) or no hallucination experiences in life (i.e. Hall-). Presence of hallucinations

was assessed with the Questionnaire for Psychotic Experiences (QPE) (Sommer et al.,

complications (SCOPA-PC) (Visser et al., 2007). As part of the UH-MEG, all patients

underwent a 5-minutes eyes-closed MEG recording, followed by assessment of

hallucinations with the QPE, loneliness by De Jong-Gierveld Loneliness (DJGL) scale (de

Jong-Gierveld and Kamphuls, 1985), depression by the Beck Depression Inventory-II

(BDI-II) (Beck et al., 1996), and cognitive testing, which included the Mini-Mental State

Examination (MMSE) as a measure of global cognitive functioning (Folstein et al., 1975),

the Trail Making Test part A (TMT-A) as a measure of motor and visual processing

speed (Reitan, 1958), and the TMT part B (TMT-B) (Crowe, 1998; Oosterman et al.,

2010; Reitan, 1992) and forward condition of the Digit Span (Lindeboom and Matto,

1994) as measures of attention. A contrast score between TMT-B and TMT-A (TMTB-

A : TMT-B minus TMT-A) was calculated as a measure of attentional set-shifting (i.e.

cognitive problem in PD (Williams-Gray et al., 2008). Hall+ and Hall- patients were

matched at the group level for age, gender, educational level, disease duration (i.e. years

Hoehn and Yahr-scale (H&Y: range 0-5 with higher scores indicating more advanced

disease severity) (Goetz et al., 2004).

All participants provided written informed consent. UH and UH-MEG were approved

Declaration of Helsinki.

After assessing the phenomenology of hallucinations with the QPE, we observed a

dichotomy in the presence of type of hallucinations within the Hall+ group. Ten patients

within the Hall+ group experienced only VH, whereas ten patients experienced

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MEG-based resting-state brain activity in PD

hallucinations in more than one modality. Therefore, we divided the Hall+ group

into subgroups (i.e. patients with only VH (unimodal Hall+, N=10) and patients with

results section for a detailed description of the phenomenology of the Hall+ patients.

2.2 MEG acquisition and preprocessing

MEG data were recorded using a 306-channel (102 magnetometers, 204 gradiometers)

whole-head MEG system (Elekta Neuromeg, Oy, Helsinki, Finland) with a sample

Hz. Five minutes of (range 262 – 400 s) eyes-closed resting-state data were recorded

with patients in supine position in the MEG-scanner inside a magnetically shielded

room (Vacuumschmelze GmbH, Hanau, Germany).

The head position relative to the MEG sensors was recorded continuously using the

as well as the outline of the patient’s scalp ( 500 points) were digitized using a 3D

digitizer (Fastrak; Polhemus, Colchester, VT, U.S.A.).

(tSSS) (Taulu and Hari, 2009; Taulu and Simola, 2006) as implemented in MaxFilter

software (Elekta Neuromeg Oy; version 2.2.15) with a sliding window of 10 seconds

and a subspace correlation limit of 0.9 was used to remove artifacts (Hillebrand

et al., 2013). The scalp surfaces of all patients were co-registered to T1-weighted

templates with 1 mm resolution, grossly matched for head-size, using a surface

matching procedure (see Supplemental Material for details). Visual inspection of the

co-registration between digitized scalp surface and the co-registered template MRI

as extracted from the co-registered template MRI was used as a volume conductor

model for source reconstruction using the beamformer approach described below.

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Chapter 6

2.3 Source reconstruction using beamforming

Neuronal activity at source-level was reconstructed using an atlas-based beamforming

approach (Hillebrand et al., 2012). The automated anatomical labeling (AAL) atlas was

used to label the voxels in a patient’s co-registered surrogate MRI in 78 cortical and

12 subcortical regions of interest (ROIs) (Tzourio-Mazoyer et al., 2002). Given the

different number of voxels in each ROI, the centroid voxel (i.e. the voxel within the

ROI that is nearest, in terms of Euclidean distance, to all other points in the ROI)

was selected as representative for that ROI (Hillebrand et al., 2016). The neuronal

activity for each centroid voxel, a so-called virtual electrode (VE), was reconstructed

as the weighted sum of each MEG sensor’s time-series. The (normalized) beamformer

equivalent current dipole in the spherical head model), and the broad-band (0.5-48 Hz)

data covariance. On average, 286 s (range 262 – 394 s) of data was used to construct

the covariance matrix. See (Hillebrand et al., 2016, 2012, 2005; Hillebrand and Barnes,

2005) for a detailed description of the beamforming approach.

The beamforming approach resulted in broad band (0.5-48 Hz) time-series for each

centroid of the 90 ROIs. From these time-series 35 epochs of 4096 samples (3.2765

s) were visually selected by MD and independently evaluated on quality by one of

the senior authors (CS). Epochs without consensus were replaced by new epochs.

The selected epochs were converted to American Standard Code for Information

Interchange (ASCII) format, and loaded into BrainWave software for further analysis

(BrainWave version 0.9.152.12.5, C. J. Stam; available at http:/home.kpn.nl/stam7883/

brainwave.html).

2.4 Spectral analysis

Peak frequency (i.e. frequency with the highest power in the 4-13 Hz range, PF), and

relative power in the frequency bands delta (0.5-4 Hz), theta (4-8 Hz), alpha1 (8-10

Hz), alpha2 (10-13 Hz), beta (13-30 Hz), and gamma (30-48 Hz) were calculated as

one average value per frequency band, and for each AAL region per epoch per patient

by using the Fast Fourier Transformation. All components of the Fourier transform

137

MEG-based resting-state brain activity in PD

outside the pass band were set to zero, after which an inverse Fourier transform was

The PF and relative power values were averaged over the 35 artefact-free epochs

per patient to obtain one value per patient per frequency band and per AAL region.

2.5 Statistical analysis

Statistical analyses were performed using IBM SPSS statistics 24.0. Patient characteristics

and spectral measures were compared between the groups. Continuous data were

tested for normality using the Shapiro-Wilk test. Normally distributed variables

were compared using independent samples T-test. Data that did not follow a normal

distribution were compared using nonparametric Mann-Whitney U test. Categorical

data were compared using the chi-square test.

To explore the spatial distribution of relative power per frequency band and PF, we

compared relative power and PF of different brain regions between the subgroups

using repeated measures ANOVA with Greenhouse-Geiser correction for sphericity,

with brain regions and frequency band as the within subject factor and group as the

between subject factor, and FDR-correction for multiple comparisons. For this analysis

the following brain regions per hemisphere were tested: frontal, central, parietal,

occipital, temporal, limbic and subcortical. For frequency bands, only the bands/PF

The False Discovery Rate (FDR) approach (Benjamini and Hochberg, 1995) with

adjusted p value (i.e., q-value) of .05 was used to correct for multiple comparisons: 1)

for the main analysis where one average value per frequency band/PF was calculated,

correction was performed for the number of frequency bands and PF, 2) for the

main analysis, power/PF was further explored regionally between the groups, and

6

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Chapter 6

Finally, Spearman correlation coefficients were calculated between each

neuropsychological test and each relative power/PF per brain region that showed

3. RESULTS

3.1 Hall+ vs. Hall- patients

3.1.1 Patient characteristics

Hall+ and Hall- patients did not differ at the group level for age, gender, educational

level, disease duration, disease severity and medication use (Table 1), which indicates

that matching was accurate. All Hall+ patients (n=20, 100%) experienced VH (Table 1).

Ten patients (n=10/20, 50%) also experienced auditory hallucinations (AH). From this

group (i.e. 10 patients with VH and AH), six patients experienced olfactory (OH) and

tactile hallucinations (TH) (n=6/20, 30%). All patients experienced recurrent complex

VH containing people, animals and inanimate objects with and without movement.

Twelve (60%) patients retained full insight, while six (30%) had partial insight into their

hallucinations and doubted the real nature of the hallucinations. Two (10%) patients

were fully convinced that their hallucinations were real (i.e. insight was absent). 80%

(n=16) of the patients had at least once interacted with their hallucinations. More than

50% of the patients also experienced minor hallucinations including visual illusions (i.e.

seeing things differently than they actually are, e.g. seeing a face in a branch of a tree),

passage hallucinations (i.e. seeing a person, animal or object passing in the peripheral

is present or nearby without being actually visible). One (5%) patient experienced

delusions in the week preceding participation in the study (Table 1).

BDI-II, and DJGL than the Hall- group (Table 1).

139

MEG-based resting-state brain activity in PD

Table 1. Patient characteristics

Hall+ (N=20) Hall- (N=20)

Age, yrs 72.15 (6.22) 70.50 (6.45)

Gender, female 7 (35.0%) 6 (30.0%)

Education level 4 (3 – 7) 7 (6 – 7)

Handedness, right 18 (90.0%) 15 (75.0%)

Disease duration, yrs 7.71 (4.35 – 12.73) 4.46 (2.75 – 9.38)

Hoehn & Yahr staging scale 3.0 (3.0 – 4.0) 3.0 (3.0 – 3.0)

LED, mg/day 882.00 (628.75 – 1188.00) 666.00 (547.25 – 1218.75) n=18

Type of hallucinations

VH 20 (100.0%)

AH 10 (50.0%)

OH 6 (30.0%)

TH 6 (30.0%)

Delusions 1 (5.0%)

BDI-II** 15.00 (10.00 – 19.75) 10.00 (5.00 – 14.75)

DJGL* 5.00 (1.00 – 6.00) 1.00 (0.00 – 4.00)

Cognition

MMSE** 26.0 (21.75 – 27.75) 28.5 (27.0 – 29.0)

Digit Span forward 8.20 (1.51) 8.85 (1.66)

TMT-A 96.47 (59.89) n=19 65.73 (58.25)

TMT-B 183.87 (113.35) n=16 121.77 (67.52) n=18

TMTB-A 101.69 (112.96) n=16 74.13 (58.16) n=18

Data are mean (SD), median (interquartile range), or n (%). Education level was assessed with the 7-item Verhage coding system for education (Verhage, 1964). Disease duration was calculated as the years diagnosed with PD at enrollment in the study. The Hoehn and Yahr staging scale was used to measure disease severity based on clinical features and functional disability. It ranges from 0-5 with higher scores indicating more advanced disease severity (Goetz et al., 2004). The total dose of dopaminergic medication (i.e. including dopaminomimetics and levodopa) was converted to a so-called levodopa equivalent dose in milligrams per day based on (Tomlinson et al., 2010). Depression was measured with the BDI-II. Loneliness was measured using the DJGL.AH: Auditory Hallucinations; BDI-II: Beck Depression Inventory-II; DJGL: De Jong Gierveld Loneliness scale; Hall+: PD patients with hallucinations; Hall-: PD patients without hallucinations; LED: Levodopa Equivalent Dose; MMSE: Mini Mental State Examination; OH: Olfactory Hallucinations; PD: Parkinson’s disease; TH: Tactile Hallucinations; TMT-A: Trail-Making Test part A; TMT-B: Trail-Making Test part B; TMTB-A: a contrast score between TMT-B and TMT-A calculated as a measure of attentional set-shifting; VH: Visual Hallucinations

6

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Chapter 6

3.1.2 Spectral analysis

Figure 1 shows the mean power spectrum for both patient groups. The Hall+ group

showed slowing of resting state brain activity compared to Hall- group, but the groups

did not differ in relative power or PF (Table 2).

Figure 1. Average power spectra over 90 AAL regions for Parkinson’s disease patients with (Hall+: yellow) and without (Hall-: blue) hallucinations. Peak frequency (i.e. frequency with the most power in the 4-13 Hz range) is lower in Hall+ compared to Hall- patients. Filled area represents the standard error of the mean.

Table 2: Relative power per frequency band in PD patients with and without hallucinations

Hall+ (n=20) Hall- (n=20) p-value

Delta 0.262 (0.074) 0.256 (0.038) .758

Theta 0.207 (0.080) 0.183 (0.054) .285

Alpha1 0.102 (0.026) 0.104 (0.034) .833

Alpha2 0.101 (0.031) 0.098 (0.018) .758

Beta 0.257 (0.090) 0.276 (0.064) .453

Gamma 0.071 (0.019) 0.082 (0.020) .089

Peak frequency 7.97 (1.15) 8.11 (0.70) .643

Power is the relative power per frequency band (delta [0.5–4 Hz], theta [4–8 Hz], alpha1 [8–10 Hz], alpha2 [10–13 Hz], beta [13–30 Hz], and gamma [30-48 Hz]). Peak frequency is the frequency with highest power in range between 4 and 13 Hz. Hall+: Parkinson’s disease patients with hallucinations; Hall-: Parkinson’s disease patients without hallucinations

141

MEG-based resting-state brain activity in PD

3.2 Subgroup analyses

3.2.1 Patient characteristics

As described above, given the dichotomy in the presence of type of hallucinations

within the Hall+ group, namely n=10 patients with only VH and n=10 patients

with multimodal hallucinations, we performed exploratory subgroup analyses and

compared PD patients with only VH (unimodal Hall+) with PD patients with multimodal

hallucinations (multimodal Hall+), and both these subgroups separately with Hall-

Unimodal Hall+, multimodal Hall+ and Hall- patients did not differ at the group level

for age, gender, educational level, disease duration, disease severity and medication use

TMT-B, and experienced more depressive symptoms and loneliness than Hall- patients.

Multimodal Hall+ patients experienced more depressive symptoms compared to Hall-

patients (Table 3). Unimodal Hall+ and multimodal Hall+ patients did not differ on

cognition, DJGL or BDI-II (Table 3).

severe (i.e. content was more often negative) in multimodal Hall+ patients and they

also experienced more often distress from their hallucinations than unimodal Hall+

patients (Table 3).

3.2.2 Spectral analysis

Figure 2 shows the mean power spectrum for the unimodal Hall+ and multimodal Hall+

patients in relation to the Hall- group. For both relative power and PF, the unimodal

Hall+ and multimodal Hall+ group deviated in opposite direction compared to the

Hall- group (Table 4). Compared to the Hall- group, unimodal Hall+ patients showed

relative power in the beta (p=.029) and gamma (p=.007) band, and lower PF (p=.011).

The relative power per AAL region for the theta, beta and gamma frequency band,

as well as PF per AAL region, are shown in Table S1-S4. After correcting for multiple

comparisons, theta, beta, and gamma band relative power, as well as PF (Table S1-S4),

6

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Chapter 6

power for the theta, beta and gamma frequency band, as well as the mean PF, for each

cortical ROI for both the unimodal Hall+ and Hall- patients.

Figure 2. Average power spectra over 90 AAL regions for Parkinson’s disease patients with only VH (unimodal Hall+: red), with multimodal (multimodal Hall+: green) and without (Hall-: blue) hallucinations. Peak frequency (i.e. frequency with the most power in the 4-13 Hz range) is lowest in unimodal Hall+ patients. Filled area represents the standard error of the mean. VH: Visual Hallucinations

143

MEG-based resting-state brain activity in PD

Tab

le 3

: Pat

ient

cha

ract

eris

tics

in P

arki

nson

’s di

seas

e pa

tient

s w

ith u

nim

odal

, mul

timod

al, a

nd w

ithou

t ha

lluci

natio

ns

Uni

mod

al H

all+

(N

=10)

Mul

tim

odal

Hal

l+ (

N=1

0)H

all-

(N

=20)

Age

, yrs

74.2

0 (5

.85)

70.1

0 (6

.17)

70.5

0 (6

.45)

Gen

der,

fem

ale

2 (2

0.0%

)5

(50.

0%)

6 (3

0.0%

)

Educ

atio

n le

vel

6.50

(3,

75 –

7.0

)4.

00 (

2.75

– 5

.50)

7.00

(6.0

– 7

.0)

Han

dedn

ess,

rig

ht9

(90.

0%)

9 (9

0.0%

)15

(75

.0%

)

Dis

ease

dur

atio

n, y

rs8.

13 (4

.81

– 19

.79)

6.46

(4.0

2 –

11.1

9)4.

46 (

2.75

– 9

.38)

Hoe

hn &

Yah

r st

agin

g sc

ale

3.5

(3.0

– 4

.0)

3.0

(2.3

8 –

4.0)

3.0

(3.0

– 3

.0)

LED

, mg/

day

922.

0 (5

75.2

5 –

1459

.75)

860.

0 (5

87.5

0 –

1056

.75)

666.

0 (5

47.2

5 –

1218

.75)

n=1

8

BDI-

II*§

16.0

(9.

75 –

21.

25)

14.5

0 (9

.75

– 18

.50)

10.0

(5.

0 –

14.7

5)

DJG

L*5.

0 (2

.50

– 6.

0)3.

50 (1

.0 –

6.0

)1.

00 (

0.0

– 4.

0)

Typ

e of

hal

luci

nati

ons

VH

10 (1

00.0

%)

10 (1

00.0

%)

AH

010

(100

.0%

)

OH

06

(60.

0%)

TH

06

(60.

0%)

Dis

tres

s fr

om h

allu

cina

tions

2 20

.0%

)5

(50.

0%)

Emot

iona

l val

ence

of h

allu

cina

tions

1 (1

0.0%

)4

(40.

0%)

Del

usio

ns0

1 (1

0.0%

)

6

144

Chapter 6

Tabl

e 3:

Con

tinue

d

Uni

mod

al H

all+

(N

=10)

Mul

tim

odal

Hal

l+ (

N=1

0)H

all-

(N

=20)

Cog

niti

on

MM

SE**

24.5

(16.

25 –

27.

0)27

.0 (

24.7

5 –

28.2

5)28

.5 (

27.0

– 2

9.0)

Dig

it Sp

an fo

rwar

d7.

90 (1

.97)

8.50

(0.

85)

8.85

(1.6

6)

TM

T-A

*11

8.89

(66.

10)

n=9

76.3

0 (4

8.33

)65

.73

(58.

25)

TM

T-B*

*24

2.43

(121

.84)

n=7

155.

63 (

75.0

8)12

1.77

(67.

52)

n=18

TM

TB

-A13

6.29

(138

.46)

n=7

97.8

8 (5

7.42

)74

.13

(58.

16)

n=18

Dat

a ar

e m

ean

(SD

), m

edia

n (in

terq

uart

ile r

ange

), or

n(%

).Edu

catio

n le

vel w

as a

sses

sed

with

the

7-it

em V

erha

ge c

odin

g sy

stem

for

educ

atio

n (V

erha

ge, 1

964)

. Dis

ease

du

ratio

n w

as c

alcu

late

d as

the

year

s di

agno

sed

with

PD

at e

nrol

lmen

t in

the

stud

y. T

he H

oehn

and

Yah

r st

agin

g sc

ale

was

use

d to

mea

sure

dis

ease

sev

erity

bas

ed o

n cl

inic

al

feat

ures

and

func

tiona

l dis

abili

ty. I

t ra

nges

from

0-5

with

hig

her

scor

es in

dica

ting

mor

e ad

vanc

ed d

isea

se s

ever

ity

(Goe

tz e

t al

., 20

04).

The

tot

al d

ose

of d

opam

iner

gic

med

icat

ion

(i.e.

incl

udin

g do

pam

inom

imet

ics

and

levo

dopa

) w

as c

onve

rted

to

a so

-cal

led

levo

dopa

equ

ival

ent

dose

in m

illig

ram

s pe

r da

y ba

sed

on (

Tom

linso

n et

al.,

20

10).

Dep

ress

ion

was

mea

sure

d w

ith t

he B

DI-

II. L

onel

ines

s w

as m

easu

red

usin

g th

e D

JGL.

BDI-

II: B

eck

Dep

ress

ion

Inve

ntor

y-II;

DJG

L: D

e Jo

ng G

ierv

eld

Lone

lines

s sc

ale;

Hal

l-: P

D p

atie

nts

with

out h

allu

cina

tions

; LED

: Lev

odop

a Eq

uiva

lent

Dos

e; M

MSE

: Min

i M

enta

l Sta

te E

xam

inat

ion;

Mul

timod

al H

all+

: PD

pat

ient

s w

ith m

ultim

odal

hal

luci

natio

ns; P

D: P

arki

nson

’s di

seas

e; T

MT-

A: T

rail-

Mak

ing

Test

par

t A

; TM

T-B:

Tra

il-M

akin

g Te

st p

art

B; T

MT

B-A

: a c

ontr

ast

scor

e be

twee

n T

MT-

B an

d T

MT-

A c

alcu

late

d as

a m

easu

re o

f att

entio

nal s

et-s

hift

ing;

Uni

mod

al H

all+

: PD

pat

ient

s w

ith o

nly

visu

al h

allu

cina

tions

;

145

MEG-based resting-state brain activity in PD

Tab

le 4

: Rel

ativ

e po

wer

per

freq

uenc

y ba

nd in

Par

kins

on’s

dise

ase

patie

nts

with

uni

mod

al, m

ultim

odal

, and

with

out

hallu

cina

tions

Uni

mod

al

Hal

l+ (

n=10

)M

ulti

mod

al

Hal

l+ (

n=10

)H

all-

(n=

20)

p-va

lue

Uni

mod

al H

all+

vs

. Hal

l-

p-va

lue

Mul

tim

odal

Hal

l+

vs. H

all-

p-va

lue

Uni

mod

al H

all+

vs.

M

ulti

mod

al H

all+

Del

ta0.

286

(0.0

93)

0.23

8 (0

.060

)0.

256

(0.0

38)

.296

.169

.315

The

ta0.

247

(0.0

56)

0.16

6 (0

.082

)0.

183

(0.0

54)

.005

*.2

67.0

19

Alp

ha1

0.09

5 (0

.027

)0.

109

(0.0

25)

0.10

4 (0

.034

).4

841.

000

.280

Alp

ha2

0.09

0 (0

.021

)0.

111

(0.0

36)

0.09

8 (0

.018

).3

03.3

28.2

18

Beta

0.21

9 (0

.062

)0.

295

(0.1

01)

0.27

6 (0

.064

).0

29*

.619

.063

Gam

ma

0.06

1 (0

.014

)0.

081

(0.0

19)

0.08

2 (0

.020

).0

07*

.948

.023

Peak

freq

uenc

y7.

31 (

0.88

)8.

63 (1

.01)

8.11

(0.

70)

.011

*.0

91.0

07*

Pow

er is

the

rel

ativ

e po

wer

per

fre

quen

cy b

and

(del

ta [

0.5–

4 H

z], t

heta

[4–

8 H

z], a

lpha

1 [8

–10

Hz]

, alp

ha2

[10–

13 H

z], b

eta

[13–

30 H

z], a

nd g

amm

a [3

0-48

Hz]

), av

erag

ed o

ver

all 9

0 A

AL

regi

ons.

Pea

k fr

eque

ncy

is t

he fr

eque

ncy

with

hig

hest

pow

er in

ran

ge b

etw

een

4 an

d 13

Hz,

ave

rage

d ov

er a

ll 90

AA

L re

gion

s.H

all-:

Par

kins

on’s

dise

ase

patie

nts

with

out

hallu

cina

tions

; Mul

timod

al H

all+

: Par

kins

on’s

dise

ase

patie

nts

with

mul

timod

al h

allu

cina

tions

; Uni

mod

al H

all+

: Par

kins

on’s

dise

ase

patie

nts

with

onl

y vi

sual

hal

luci

natio

ns

6

146

Chapter 6

Figure 3. Mean relative power for each region of interest (ROI) in unimodal Hall+ (left) and Hall- (right) patients displayed as a color-coded map on a parcellated template brain viewed from, in clockwise order, the left, top, right, right-midline and left-midline. Panel A: rela-tive power in the theta band. Panel B: relative power in the beta band. Panel C: relative power in the gamma band. Panel D: Peak frequency. Hot and cold colors indicate higher and

-ing subcortical regions per frequency band and for all the relative power and peak frequency values in the two groups.Hall-: Parkinson’s disease patients without hallucinations; unimodal Hall+: Parkinson’s disease patients with only visual hallucinations

147

MEG-based resting-state brain activity in PD

In the theta band, unimodal Hall+ patients showed higher relative power in 74 (82.2%)

out of 90 AAL regions compared to the Hall- group. These regions were spread across

the entire brain and included all the regions in the limbic lobes and all the subcortical

regions in both hemispheres (Table S1). In the beta band, relative power was lower in

14 (15.6%) out of 90 AAL regions in unimodal Hall+ patients. These regions were mainly

located in the parietal and occipital lobes (Table S2). In the gamma band, unimodal

Hall+ patients showed lower relative power in 47 (52.2%) out of 90 AAL regions.

These regions included mainly the frontal and limbic lobes, and subcortical regions, but

not the temporal, parietal and occipital lobes (Table S3). PF was lower in 51 (56.7%)

out of 90 AAL regions in unimodal Hall+ patients compared to Hall- patients. These

regions comprised almost the entire brain except (mainly) the frontal lobes (Table S4).

To explore whether a potential spatial pattern could be found for the AAL regions

located across the right hemisphere, and comprised the parietal, temporal, limbic and

PF included left occipital and limbic brain region, whereas in the right hemisphere, all

6

148

Chapter 6

Figure 4. unimodal Hall+ and Hall- patients, displayed as in Figure 3, for the theta (panel A), beta (panel B), and gamma (panel C) band, and for peak frequency (panel D). Red: higher relative power in unimodal Hall+ patients. Blue: lower relative power/peak frequen-cy in unimodal Hall+ patients. Gray: brain regions that did not differ between the groups.

-

and table S5 for the mean relative power/peak frequency values in the two groups. Hall-: Parkinson’s disease patients without hallucinations; unimodal Hall+: Parkinson’s disease patients with only visual hallucinations

The multimodal Hall+ and Hall- groups did not differ in relative power or PF (Table

power in the theta (p=0.19) and gamma (p=.023) frequency band and in PF (p=.007).

multimodal Hall+ patients showing higher PF than unimodal Hall+ patients (Table 4).

The relative power per AAL region for the theta and gamma band and PF are shown

in Table S7-S9.

149

MEG-based resting-state brain activity in PD

Further regional exploration showed that in the theta band, all but the bilateral central,

Hall+ and multimodal Hall+ group (Table S5-S6, Figure 5a). In the gamma band, relative

Figure 5. Distribution of the brain regions that showed significant difference be-tween unimodal Hall+ and multimodal Hall+ patients, displayed as in Figure 3, for the theta (panel A), and gamma (panel B) band, and for peak frequency (panel C). Red: higher relative power in unimodal Hall+ patients. Blue: lower relative power/peak fre-quency in unimodal Hall+ patients. Gray: brain regions that did not differ between the

-

groups and table S5 for the mean relative power/peak frequency values in the two groups. Multimodal Hall+: Parkinson’s disease patients with multimodal hallucinations; unimodal Hall+: Parkinson’s disease patients with only visual hallucinations

6

150

Chapter 6

Although the subgroups did not differ in use of medication (Table 3), we redid the main

analyses in the subgroups (Table 4) with medication (LED) as a covariate in order to

exclude a potential effect of medication on our results, and found that the corrected

model still showed the same effects (see Table S10).

3.2.3 Correlation with neuropsychological tests

3.2.3.1 MMSE

In the Hall- group, a negative correlation was found between relative power in the

right parietal and limbic brain region in the theta band and MMSE (Table 5). In the beta

band, MMSE was positively correlated with relative power in the right parietal brain

region (Table 5). MMSE was positively correlated with PF in all but the right occipital

the unimodal Hall+ group.

3.2.3.2 TMT-A and TMT-B

In the Hall- group, Spearman correlation showed a positive correlation between both

the TMT-A and TMT-B and relative power in all brain regions in the theta band, and

negative correlations with relative power in brain regions in the beta band (Table 5).

For PF, a negative correlation was found between all brain regions and TMT-A, whereas

band or the unimodal Hall+ group.

151

MEG-based resting-state brain activity in PD

Table 5: region and neuropsychological tests in Parkinson’s disease patients without hallucinations

Brain region Neuropsychological test N Spearman rho (r) p-value

Theta band

Right parietal MMSE 20 -0.45 .048

TMT-A 20 0.51 .023

TMT-B 18 0.53 .025

Right temporal MMSE 20 -0.44 .054

TMT-A 20 0.51 .020

TMT-B 18 0.51 .032

Right limbic MMSE 20 -0.45 .049

TMT-A 20 0.53 .016

TMT-B 18 0.47 .049

Right subcortical MMSE 20 -0.43 .062

TMT-A 20 0.55 .011

TMT-B 18 0.51 .029

Beta band

Right parietal MMSE 20 0.51 .021

TMT-A 20 -0.61 .004

TMT-B 18 -0.60 .008

Right temporal MMSE 20 0.44 .054

TMT-A 20 -0.49 .029

TMT-B 18 -0.62 .007

Gamma band

Left frontal MMSE 20 -0.01 .966

TMT-A 20 0.10 .669

TMT-B 18 0.18 .464

Right frontal MMSE 20 -0.05 .824

TMT-A 20 0.19 .433

TMT-B 18 0.20 .432

Left central MMSE 20 -0.18 .436

TMT-A 20 0.33 .160

TMT-B 18 0.14 .569

Left limbic MMSE 20 -0.05 .844

TMT-A 20 0.13 .599

TMT-B 18 0.12 .641

6

152

Chapter 6

Table 5: Continued

Brain region Neuropsychological test N Spearman rho (r) p-value

Peak frequency

Right parietal MMSE 20 0.55 .012

TMT-A 20 -0.55 .012

TMT-B 18 -0.44 .069

Left occipital MMSE 20 0.51 .023

TMT-A 20 -0.56 .010

TMT-B 18 -0.59 .011

Right occipital MMSE 20 0.41 .076

TMT-A 20 -0.47 .035

TMT-B 18 -0.50 .034

Right temporal MMSE 20 0.46 .042

TMT-A 20 -0.56 .010

TMT-B 18 -0.46 .056

Left limbic MMSE 20 0.57 .008

TMT-A 20 -0.66 .001

TMT-B 18 -0.48 .043

Right limbic MMSE 20 0.64 .002

TMT-A 20 -0.65 .002

TMT-B 18 -0.44 .068

Right subcortical MMSE 20 0.57 .009

TMT-A 20 -0.61 .005

TMT-B 18 -0.33 .184

MMSE: Mini-Mental State Examination; TMT-A: Trail-Making Test part A; TMT-B: Trail-Making Test part B

4. DISCUSSION

oscillatory brain activity in PD patients who experienced visual hallucinations, the

PD patients with and without hallucinations. However, remarkable results were found

when exploratory subgroup analyses were performed after dissecting the hallucinating

group into purely visual hallucinations (unimodal Hall+) and hallucinations also in other

153

MEG-based resting-state brain activity in PD

modalities (multimodal Hall+). Compared to patients without hallucinations, patients

with only VH showed slowing of resting-state oscillatory brain activity, with spatial

distributions characterized by an increase in theta power in all but the fronto-central

and occipital brain region in the right hemisphere, and concomitant decrease in beta

power in the right temporoparietal brain region, and decrease in gamma power in

the bilateral frontal and left limbic brain region, and lowering of PF in almost all but

the frontal brain regions. These deviations were absent in the patient group with

multimodal hallucinations compared to patients without hallucinations. Compared to

and diffuse increase in PF in all but the frontal brain regions.

Analysis of relative power/PF in relation to performance on neuropsychological tests

showed, only in patients without hallucinations, a correlation between higher theta

power and worse performance on the MMSE, better performance on MMSE and

higher beta power in the right parietal region and higher PF in all but the right occipital

brain regions. Lower theta and higher beta power were associated with a better

performance on both TMT-A and TMT-B, whereas a diffuse higher PF was associated

with a better performance on TMT-A, and higher PF in bilateral occipital and left limbic

brain region was associated with better performance on the TMT-B test.

4.2 Underlying mechanism(s) of unimodal visual and multimodal hallucinations in PD

4.2.1 Unimodal visual hallucinations

The cholinergic system is seen as a modulator of the cortical signal-to-noise ratio

(Collerton et al., 2005). Slowing in resting-state brain activity (increased power in

delta and theta frequencies and decreased power in alpha and beta frequencies) has

been associated with impaired cholinergic function (Bauer et al., 2012a; Simpraga et

al., 2018). As mentioned earlier, the central cholinergic system has been involved in

the integration of top-down attentional and bottom-up sensory processing such that

cholinergic dysfunction (results in decrease in signal-to-noise ratio) may increase the

uncertainty in top-down activity resulting in incorrect scene representation, and thus

hallucinations (Collerton et al., 2005; Friston, 2005). Indeed, impaired bottom-up (i.e.

6

154

Chapter 6

reduced activation of the visual pathways) and top-down (i.e. defective attentional)

processing, and thus cholinergic dysfunction, has frequently been reported in PD

patients who experience VH (Boecker et al., 2007; Dagmar H. Hepp et al., 2017; Matsui

et al., 2006; Meppelink et al., 2009; Park et al., 2013; Stebbins et al., 2004). Recently,

Hepp et al. proposed that impaired bottom-up visual processing in combination with

defective top-down attentional processing may underlie VH in PD (Dagmar H. Hepp

evidence that VH in PD may emerge due to central cholinergic dysfunction.

With respect to spatial distribution, compared to patients without hallucinations,

groups were located in the right hemisphere and comprised the temporoparietal brain

areas, amongst others. The right hemisphere has been shown to play a role in arousal

and attentional processes and mediate top-down attentional processing (Levy and

Wagner, 2011; Posner, 1994; Sacchet et al., 2015). The temporoparietal brain regions

form part of the ventral attentional network (VAN, also named salience network),

which is lateralized to the right hemisphere and involved in shifting attention in the

presence of salient stimuli (Corbetta et al., 2002; Vossel et al., 2014). Moreover, the

right temporoparietal brain regions have been involved in source monitoring or ‘self-

other’ distinction (i.e. discrimination between external perceptions and internally

have been reported in PD patients with VH (Barnes et al., 2003; Muller et al., 2014).

Beta band activity has been associated with long-range feedback or top-down

2000; Michalareas et al., 2016). Theta band activity has also been proposed in top-down

processing with a key inhibitory role in working memory to suppress task-irrelevant

or distracting information in situations that demand cognitive control (Klimesch,

1999; Nigbur et al., 2011). Moreover, increase in theta oscillations is observed during

lower vigilance and states of drowsiness (Strijkstra et al., 2003). In patients without

hallucinations, we found that higher power in the right temporoparietal regions

155

MEG-based resting-state brain activity in PD

in the theta band was correlated with worse performance on the tests for visual

processing speed (TMT-A) and attention (TMT-B), whereas higher power in the right

temporoparietal regions in the beta band was associated with better performance on

both tests (Table 5). These correlations were lacking in patients with only VH, which

might be due to the small sample size of the group (data available in n=9 for TMT-A

and n=7 for TMT-B). Taken together, our results provide support for alterations in

top-down attentional processing in PD patients with VH.

Gamma band activity is generated in early sensory cortices, and involved in feedforward

or bottom-up processing (Bastos et al., 2015; Herrmann et al., 2010; N Kopell et

regions between PD patients with unimodal VH and PD patients without hallucinations

suggests that there may be no alterations in bottom-up processing in PD patients with

only VH. Less straightforward is the interpretation of decreased gamma power in the

frontal brain regions in PD patients with only VH compared to PD patients without

hallucinations. Gamma oscillations are modulated by various cognitive processes such

mechanisms of the brain. Particularly, gamma oscillations are involved in working

memory storage that can be controlled by beta oscillations, such that beta rhythm

regulates the access of sensory information into working memory and controls its

maintenance (Herrmann et al., 2010; Miller et al., 2018). Hence, decreased gamma

power in the frontal brain regions might be a consequence of decreased beta power

and thus top-down processing. However, several other brain regions also showed

higher power in the theta and lower power in the gamma band, and lower PF in

patients with only VH, hence our results with respect to spatial distribution may not

pathophysiological mechanisms of VH and should be interpreted with caution. Future

work to evaluate MEG-based functional connectivity and brain network organization

may be of additional value in exploring the exact role of multiple brain regions and

networks - involved in attention and perception - in the pathophysiology of VH.

6

156

Chapter 6

Another possible explanation for slowing of resting-state brain activity in patients with

only VH as opposed to patients with multimodal hallucinations and patients without

hallucinations may be sought in the patient characteristics of the groups. Although

longer disease duration at enrollment and were slightly more cognitively impaired than

patients with multimodal hallucinations and patients without hallucinations, indicating a

slightly more advanced disease stage in patients with only VH. For decades, diffuse and

local slowing of resting state oscillatory brain activity, involving increases in theta power

and decreases in beta and gamma power, has been a consistently reported feature in

PD patients, with severity of slowing increasing with advancing disease, and predicting

risk of future dementia (Bosboom et al., 2006; Caviness et al., 2007; Fonseca et al.,

2009; Klassen et al., 2011; Neufeld et al., 1994; Olde Dubbelink et al., 2014b, 2013a;

Serizawa et al., 2008; Soikkeli et al., 1991; Stoffers et al., 2007).

4.2.2 Multimodal hallucinations

Patients with multimodal hallucinations experienced both VH and AH (with similar

prevalences) and hallucinations in other modalities but did not show more slowing

of resting-state brain activity than patients with only VH or patients without

hallucinations. Patients with multimodal hallucinations rather showed faster, although

without hallucinations, which indicates the complexity of the pathophysiology of

hallucinations in PD. In addition, given the extensive differences in spatial distribution

in the different frequency bands/PF between patients with multimodal hallucinations

A likely candidate to explain changes in spectral power in PD patients with multimodal

hallucinations may be the dopaminergic system. Research on the effect of dopaminergic

neurotransmission on resting-state oscillatory brain activity in PD is scarce.

Nonetheless, a few studies have examined the effect of exposure to dopaminergic

agents (i.e. dopaminomimetics or dopamine precursor levodopa (L-dopa)) on resting-

state brain activity in PD patients and found contradicting results (Babiloni et al., 2018;

157

MEG-based resting-state brain activity in PD

J. M. Melgari et al., 2014; Stoffers et al., 2007; Yaar and Shapiro, 1983). A previous

quantitative EEG study examined 25 PD patients on chronic L-dopa therapy and found

region (Yaar and Shapiro, 1983). In addition, Melgari et al (2014) obtained resting-state

source-space EEG recordings in 24 PD patients before and after an oral dose of L-dopa

Babiloni et al (2018), who studied resting-state EEG activity in PD patients with normal

(n=35) and impaired cognition (n=85) before and after L-dopa intake and compared

these data with EEGs from healthy individuals (n=50). Compared to the healthy

individuals, the PD groups with and without cognitive decline showed a diffuse increase

in delta power and decrease in alpha power in the posterior brain regions. In relation

to PD patients with normal cognition, cognitively impaired PD patients showed greater

increase in delta power, greater reduction in occipital alpha power with concomitant

increase in alpha power in the frontal, central and temporal brain regions (Babiloni

et al., 2018). Notably, an MEG-study by Stoffers et al in non-demented PD patients

power (Stoffers et al., 2007). Thus, there is considerable variability in the reported

relation between resting-state brain activity and dopaminergic neurotransmission,

which could be related to the demographics of the patient groups or methodological

differences between the studies.

patients with only VH, patients with multimodal hallucinations, and patients without

hallucinations (Table 3). Nonetheless, psychosis has frequently been reported as a

non-motor adverse effect of dopaminergic treatment in both early-stage and late-stage

PD (Barrett et al., 2017; Morgante et al., 2012; Ravina et al., 2007; Stowe et al., 2008).

subthalamic deep brain stimulation, which could probably be related to the reduction

dopaminergic treatment in PD may lead to psychosis, and that restoration of brain

6

158

Chapter 6

dopamine levels by drug treatment may (at least partly) restore normal patterns of

oscillatory brain activity, suggest that hyperdopaminergic neurotransmission may

underlie psychosis in PD and does not induce slowing in resting-state oscillatory brain

activity.

A highly speculative explanation for the increase in signal power in patients with

multimodal hallucinations may be sought in the decreased output from the nigrostriatal

dopaminergic system to connected brain areas. The dopamine depleted nigro-striatal-

thalamo-cortical circuit in PD may lead to reduced modulatory control on connected

cortical brain regions (J. M. Melgari et al., 2014; Rodriguez-Oroz et al., 2009). In

response, connected brain areas may lower their detection threshold for neuronal

towards incoming signals) within the connected brain regions. This hyper-excitability

without the presence of an external source; a hallucination (dependent on the

(Carter and ffytche, 2015). Dysregulation of neural circuits due to imbalance between

excitation and inhibition as a general model of hallucinations has been proposed in both

hallucinations (Jardri et al., 2016).

Alterations in serotonin neurotransmission have also been proposed in the

(Factor et al., 2017). Treatment with pimavanserin, a serotonin 2A inverse-agonist,

has been shown to alleviate psychosis in both PD patients with normal and impaired

cognitive functioning (Espay et al., 2018; Kianirad and Simuni, 2017). To date, only one

study has examined in vivo changes in serotonin receptor binding in PD with positron

emission tomography (PET) and found increased serotonin binding in the ventral

visual pathway in PD patients with VH compared to patients without hallucinations

(Ballanger et al., 2010). The use of selective serotonin reuptake inhibitors (SSRIs)

(increasing the extracellular level of serotonin) has been associated with changes in

rhythmic brain activity in the delta, theta and alpha band in prefrontal brain regions,

159

MEG-based resting-state brain activity in PD

with decreases in the delta and theta band and increases in the alpha band (Bares et al.,

were widespread throughout the brain in both patients with only VH and patients with

lower relative power in the theta band compared to both patients with only VH and

patients without hallucinations, hinting that serotonergic dysfunction may play a role

in multimodal hallucinations in PD.

provide strong support for the notion that dopaminergic or serotonergic dysfunction

may induce faster resting-state brain activity in PD patients with multimodal

hallucinations. Future studies investigating different modalities of hallucinations within

PD are needed to gain insight into other potential underlying mechanisms.

4.3 Strengths and limitations

A strength of this study is that it investigated hallucinations in PD with source-space

Second, both patients with and without hallucinations, as well as, patients with only VH

and patients with multimodal hallucinations, were carefully matched for age, gender,

educational level, disease duration, disease stage, and use of medication, which makes

This study also has limitations. First, by performing subgroup analyses we reduced the

sample size of the hallucination group, and therefore, the results should be interpreted

with caution. However, by dividing patients with hallucinations in subgroups based

group differences to the pathophysiology of VH. Second, cholinesterase inhibitors

with simultaneous decreases in low frequency power (Fogelson et al., 2003). We

observed the opposite pattern in our patients. In our study, only two patients (n=1 in

the unimodal Hall+ group and n=1 in the Hall- group) used the cholinesterase inhibitor

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rivastigmine. Therefore, it is unlikely that the use of cholinesterase inhibitors has

are also used to treat psychosis in PD (Wilby et al., 2017), and have been shown to

increase power in lower frequencies and decrease power in higher frequencies (Hyun

et al., 2011; Maccrimmon et al., 2012). In our study, only two patients with multimodal

hallucinations used atypical antipsychotics (n=1 clozapine, and n=1 quetiapine). As we

found decreased power in the delta and theta band, and increases in power in the alpha

and beta band in patients with multimodal hallucinations, it is unlikely that the use of

5. CONCLUSION

Source-space MEG shows distinct spectral differences between Parkinson’s disease

patients with unimodal visual hallucinations and patients without hallucinations.

Slowing of resting-state brain activity with increases in theta activity, and concomitant

decreases in beta and gamma activity indicates central cholinergic dysfunction as

underlying mechanism of visual hallucinations in Parkinson’s disease. Future work to

evaluate functional connectivity and brain network organization is needed in order to

explore the exact role of multiple brain regions and networks - involved in attention

and perception – in the pathophysiology of visual hallucinations in Parkinson’s disease.

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SUPPLEMENTAL MATERIAL

Methods

Co-registration

The scalp surfaces of all patients were co-registered to a T1-weighted MNI template

with 1 mm resolution using a surface matching procedure. For this, the T1-weighted

average structural MNI template from the SPM toolbox was used (Douw et al., 2018).

This matching was repeated with templates of different sizes (i.e. very small, small,

medium, and large). The small, medium and large templates had been created from

77 MRIs from the Amsterdam Dementia Cohort (ADC) (Van Der Flier et al., 2014),

MRIs. The subjects were split in quartiles based on the size of the ellipsoid (= the length

of the ellipsoid-axis pointing in the y-direction, i.e. roughly through the nose). The

1st

the other 2 quartiles for the medium template (N=39). The MRIs were aligned using

DARTEL toolbox in SPM and averaged. Lastly, 9 MRIs from people with very small

heads were selected from the ADC and aligned to create a very small template. The

a surrogate MRI for that patient.

Normalization MEG spectra

power value over all epochs and all subject. Subsequently, the curves for each epoch

and each subject were divided by this maximum value. Finally, the mean and standard

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Results

Table S1: Relative power per AAL region in the theta band in Parkinson’s disease patients with unimodal hallucinations and patients without hallucinations

AAL region Unimodal Hall+ (n=10)

Hall- (n=20) p-value

1 Gyrus rectus L 0.211 (0.046) 0.167 (0.045) .021

2 Olfactory cortex L 0.241 (0.054) 0.183 (0.051) .007

3 Superior frontal gyrus, orbital part L 0.201 (0.051) 0.162 (0.037) .023

4 Superior frontal gyrus, medial orbital part L 0.206 (0.052) 0.161 (0.036) .009

5 Middle frontal gyrus, orbital part L 0.189 (0.055) 0.161 (0.041) .132

6 Inferior frontal gyrus, orbital part L 0.206 (0.051) 0.170 (0.050) .077

7 Superior frontal gyrus L, dorsolateral 0.208 (0.044) 0.170 (0.038) .020

8 Middle frontal gyrus L 0.206 (0.057) 0.167 (0.040) .039

9 Inferior frontal gyrus, opercular part L 0.212 (0.062) 0.166 (0.052) .045

10 Inferior frontal gyrus, triangular part L 0.206 (0.059) 0.162 (0.044) .027

11 Superior frontal gyrus, medial part L 0.222 (0.047) 0.171 (0.039) .004

12 Supplementary motor area L 0.211 (0.052) 0.170 (0.036) .016

13 Paracentral lobule L 0.181 (0.054) 0.166 (0.037) .364

14 Precentral gyrus L 0.195 (0.060) 0.160 (0.037) .059

15 Rolandic operculum L 0.245 (0.065) 0.177 (0.061) .009

16 Postcentral gyrus L 0.194 (0.065) 0.155 (0.047) .070

17 Superior parietal gyrus L 0.232 (0.063) 0.178 (0.061) .031

18 Inferior parietal gyri L 0.232 (0.067) 0.170 (0.060) .015

19 Supramarginal gyrus L 0.245 (0.069) 0.181 (0.084) .041

20 Angular gyrus L 0.285 (0.081) 0.202 (0.098) .027

21 Precuneus L 0.250 (0.064) 0.187 (0.063) .017

22 Superior occipital gyrus L 0.281 (0.078) 0.202 (0.080) .016

23 Middle occipital gyrus L 0.297 (0.802) 0.222 (0.106) .059

24 Inferior occipital gyrus L 0.302 (0.094) 0.247 (0.098) .154

0.291 (0.077) 0.216 (0.077) .018

26 Cuneus L 0.284 (0.078) 0.201 (0.073) .008

27 Lingual gyrus L 0.306 (0.083) 0.227 (0.082) .019

28 Fusiform gyrus L 0.308 (0.087) 0.235 (0.099) .058

29 Heschl gyrus L 0.271 (0.072) 0.190 (0.076) .009

30 Superior temporal gyrus L 0.263 (0.073) 0.185 (0.074) .012

31 Middle temporal gyrus L 0.290 (0.095) 0.202 (0.099) .027

32 Inferior temporal gyrus L 0.281 (0.081) 0.210 (0.085) .036

33 Temporal pole: superior temporal gyrus L 0.236 (0.061) 0.183 (0.058) .029

34 Temporal pole: middle temporal gyrus L 0.234 (0.054) 0.187 (0.057) .038

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Table S1: Continued

AAL region Unimodal Hall+ (n=10)

Hall- (n=20) p-value

35 Parahippocampal gyrus L 0.282 (0.071) 0.206 (0.067) .007

36 Anterior cingulate and paracingulate gyri L 0.238 (0.056) 0.176 (0.046) .003

37 Median cingulate and paracingulate gyri L 0.240 (0.059) 0.184 (0.048) .009

38 Posterior cingulate gyrus L 0.269 (0.060) 0.196 (0.060) .004

39 Insula L 0.239 (0.061) 0.176 (0.050) .006

40 Gyrus rectus R 0.210 (0.045) 0.164 (0.039) .007

41 Olfactory cortex R 0.239 (0.053) 0.181 (0.049) .006

42 Superior frontal gyrus, orbital part R 0.196 (0.045) 0.157 (0.032) .011

43 Superior frontal gyrus, medial orbital part R 0.204 (0.048) 0.159 (0.032) .005

44 Middle frontal gyrus, orbital part R 0.184 (0.060) 0.152 (0.029) .133

45 Inferior frontal gyrus, orbital part R 0.200 (0.057) 0.164 (0.046) .076

46 Superior frontal gyrus R, dorsolateral 0.206 (0.045) 0.165 (0.038) .013

47 Middle frontal gyrus R 0.195 (0.048) 0.156 (0.039) .023

48 Inferior frontal gyrus, opercular part R 0.200 (0.045) 0.155 (0.042) .014

49 Inferior frontal gyrus, triangular part R 0.204 (0.056) 0.148 (0.038) .004

50 Superior frontal gyrus, medial part R 0.216 (0.049) 0.164 (0.036) .003

51 Supplementary motor area R 0.201 (0.046) 0.166 (0.038) .036

52 Paracentral lobule R 0.186 (0.055) 0.159 (0.036) .111

53 Precentral gyrus R 0.195 (0.036) 0.158 (0.051) .048

54 Rolandic operculum R 0.259 (0.066) 0.172 (0.079) .005

55 Postcentral gyrus R 0.213 (0.054) 0.156 (0.059) .016

56 Superior parietal gyrus R 0.251 (0.067) 0.172 (0.055) .002

57 Inferior parietal gyri R 0.264 (0.086) 0.171 (0.072) .004

58 Supramarginal gyrus R 0.283 (0.080) 0.167 (0.074) .000

59 Angular gyrus R 0.298 (0.090) 0.189 (0.087) .003

60 Precuneus R 0.283 (0.083) 0.191 (0.063) .002

61 Superior occipital gyrus R 0.291 (0.076) 0.202 (0.082) .007

62 Middle occipital gyrus R 0.313 (0.093) 0.218 (0.089) .011

63 Inferior occipital gyrus R 0.294 (0.081) 0.220 (0.084) .030

0.297 (0.079) 0.213 (0.079) .011

65 Cuneus R 0.291 (0.076) 0.196 (0.067) .002

66 Lingual gyrus R 0.300 (0.077) 0.217 (0.079) .011

67 Fusiform gyrus R 0.287 (0.078) 0.222 (0.087) .056

68 Heschl gyrus R 0.292 (0.071) 0.180 (0.082) .001

69 Superior temporal gyrus R 0.305 (0.092) 0.177 (0.082) .001

70 Middle temporal gyrus R 0.315 (0.109) 0.200 (0.097) .006

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Table S1: Continued

AAL region Unimodal Hall+ (n=10)

Hall- (n=20) p-value

71 Inferior temporal gyrus R 0.271 (0.075) 0.199 (0.093) .044

72 Temporal pole: superior temporal gyrus R 0.230 (0.056) 0.177 (0.063) .031

73 Temporal pole: middle temporal gyrus R 0.230 (0.055) 0.168 (0.057) .008

74 Parahippocampal gyrus R 0.274 (0.070) 0.196 (0.064) .005

75 Anterior cingulate and paracingulate gyri R 0.229 (0.057) 0.173 (0.042) .005

76 Median cingulate and paracingulate gyri R 0.229 (0.054) 0.177 (0.046) .010

77 Posterior cingulate gyrus R 0.281 (0.067) 0.193 (0.057) .001

78 Insula R 0.244 (0.068) 0.176 (0.058) .008

79 Hippocampus L 0.282 (0.067) 0.214 (0.078) .026

80 Hippocampus R 0.287 (0.071) 0.196 (0.073) .003

81 Amygdala L 0.262 (0.069) 0.199 (0.064) .019

82 Amygdala R 0.259 (0.064) 0.192 (0.063) .011

83 Caudate nucleus L 0.241 (0.052) 0.186 (0.052) .012

84 Caudate nucleus R 0.247 (0.052) 0.181 (0.048) .002

85 Lenticular nucleus, putamen L 0.248 (0.060) 0.189 (0.058) .014

86 Lenticular nucleus, putamen R 0.250 (0.064) 0.182 (0.051) .003

87 Lenticular nucleus, pallidum L 0.264 (0.067) 0.201 (0.066) .021

88 Lenticular nucleus, pallidum R 0.256 (0.063) 0.188 (0.053) .004

89 Thalamus L 0.251 (0.057) 0.197 (0.060) .024

90 Thalamus R 0.261 (0.053) 0.190 (0.058) .003

Parkinson’s disease patients without hallucinations; Unimodal Hall+: Parkinson’s disease patients with only visual hallucinations

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Table S2: Relative power per AAL region in the beta band in Parkinson’s disease patients with unimodal hallucinations and patients without hallucinations

AAL region Unimodal Hall+ (n=10)

Hall- (n=20) p-value

1 Gyrus rectus L 0.213 (0.056) 0.253 (0.054) .069

2 Olfactory cortex L 0.210 (0.058) 0.256 (0.063) .061

3 Superior frontal gyrus, orbital part L 0.231 (0.056) 0.262 (0.049) .126

4 Superior frontal gyrus, medial orbital part L 0.223 (0.051) 0.264 (0.041) .025

5 Middle frontal gyrus, orbital part L 0.233 (0.059) 0.264 (0.056) .169

6 Inferior frontal gyrus, orbital part L 0.231 (0.078) 0.262 (0.050) .193

7 Superior frontal gyrus L, dorsolateral 0.270 (0.071) 0.294 (0.051) .307

8 Middle frontal gyrus L 0.279 (0.089) 0.300 (0.064) .452

9 Inferior frontal gyrus, opercular part L 0.294 (0.102) 0.319 (0.062) .411

10 Inferior frontal gyrus, triangular part L 0.277 (0.100) 0.300 (0.061) .437

11 Superior frontal gyrus, medial part L 0.237 (0.069) 0.273 (0.046) .101

12 Supplementary motor area L 0.281 (0.077) 0.310 (0.056) .248

13 Paracentral lobule L 0.311 (0.064) 0.310 (0.056) .946

14 Precentral gyrus L 0.329 (0.099) 0.341 (0.062) .667

15 Rolandic operculum L 0.256 (0.080) 0.304 (0.064) .085

16 Postcentral gyrus L 0.308 (0.077) 0.352 (0.065) .117

17 Superior parietal gyrus L 0.224 (0.058) 0.305 (0.089) .006

18 Inferior parietal gyri L 0.241 (0.069) 0.329 (0.095) .015

19 Supramarginal gyrus L 0.238 (0.066) 0.316 (0.096) .028

20 Angular gyrus L 0.173 (0.070) 0.276 (0.112) .013

21 Precuneus L 0.210 (0.054) 0.292 (0.085) .003

22 Superior occipital gyrus L 0.152 (0.043) 0.242 (0.102) .002

23 Middle occipital gyrus L 0.144 (0.056) 0.239 (0.114) .005

24 Inferior occipital gyrus L 0.143 (0.059) 0.210 (0.103) .067

0.138 (0.039) 0.218 (0.089) .002

26 Cuneus L 0.137 (0.036) 0.233 (0.090) .000

27 Lingual gyrus L 0.145 (0.047) 0.219 (0.096) .030

28 Fusiform gyrus L 0.156 (0.060) 0.232 (0.096) .029

29 Heschl gyrus L 0.224 (0.068) 0.295 (0.089) .037

30 Superior temporal gyrus L 0.213 (0.075) 0.289 (0.084) .023

31 Middle temporal gyrus L 0.180 (0.069) 0.260 (0.100) .032

32 Inferior temporal gyrus L 0.178 (0.065) 0.244 (0.087) .043

33 Temporal pole: superior temporal gyrus L 0.219 (0.069) 0.263 (0.056) .065

34 Temporal pole: middle temporal gyrus L 0.204 (0.054) 0.247 (0.052) .040

35 Parahippocampal gyrus L 0.190 (0.070) 0.247 (0.074) .057

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Table S2: Continued

AAL region Unimodal Hall+ (n=10)

Hall- (n=20) p-value

36 Anterior cingulate and paracingulate gyri L 0.230 (0.077) 0.274 (0.055) .087

37 Median cingulate and paracingulate gyri L 0.266 (0.071) 0.300 (0.064) .197

38 Posterior cingulate gyrus L 0.211 (0.060) 0.279 (0.079) .023

39 Insula L 0.258 (0.087) 0.303 (0.068) .132

40 Gyrus rectus R 0.212 (0.057) 0.251 (0.057) .086

41 Olfactory cortex R 0.210 (0.062) 0.259 (0.063) .053

42 Superior frontal gyrus, orbital part R 0.223 (0.065) 0.255 (0.053) .159

43 Superior frontal gyrus, medial orbital part R 0.224 (0.064) 0.257 (0.048) .117

44 Middle frontal gyrus, orbital part R 0.225 (0.055) 0.257 (0.046) .099

45 Inferior frontal gyrus, orbital part R 0.238 (0.082) 0.267 (0.053) .338

46 Superior frontal gyrus R, dorsolateral 0.280 (0.080) 0.304 (0.054) .337

47 Middle frontal gyrus R 0.300 (0.107) 0.317 (0.066) .662

48 Inferior frontal gyrus, opercular part R 0.296 (0.107) 0.326 (0.074) .434

49 Inferior frontal gyrus, triangular part R 0.272 (0.099) 0.307 (0.066) .253

50 Superior frontal gyrus, medial part R 0.243 (0.076) 0.272 (0.044) .293

51 Supplementary motor area R 0.292 (0.079) 0.319 (0.064) .323

52 Paracentral lobule R 0.314 (0.084) 0.319 (0.064) .849

53 Precentral gyrus R 0.314 (0.094) 0.346 (0.070) .291

54 Rolandic operculum R 0.232 (0.063) 0.305 (0.078) .017

55 Postcentral gyrus R 0.271 (0.073) 0.364 (0.097) .013

56 Superior parietal gyrus R 0.216 (0.054) 0.299 (0.080) .006

57 Inferior parietal gyri R 0.191 (0.063) 0.309 (0.103) .001

58 Supramarginal gyrus R 0.207 (0.081) 0.322 (0.107) .006

59 Angular gyrus R 0.156 (0.053) 0.271 (0.107) .000

60 Precuneus R 0.195 (0.060) 0.276 (0.082) .010

61 Superior occipital gyrus R 0.154 (0.054) 0.248 (0.102) .002

62 Middle occipital gyrus R 0.135 (0.051) 0.236 (0.105) .001

63 Inferior occipital gyrus R 0.146 (0.058) 0.220 (0.089) .024

0.141 (0.051) 0.216 (0.090) .023

65 Cuneus R 0.148 (0.050) 0.231 (0.088) .003

66 Lingual gyrus R 0.139 (0.054) 0.223 (0.095) .016

67 Fusiform gyrus R 0.157 (0.060) 0.232 (0.094) .030

68 Heschl gyrus R 0.200 (0.061) 0.286 (0.088) .010

69 Superior temporal gyrus R 0.175 (0.061) 0.273 (0.100) .009

70 Middle temporal gyrus R 0.153 (0.057) 0.254 (0.103) .007

71 Inferior temporal gyrus R 0.171 (0.053) 0.243 (0.089) .026

72 Temporal pole: superior temporal gyrus R 0.221 (0.064) 0.262 (0.066) .123

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Table S2: Continued

AAL region Unimodal Hall+ (n=10)

Hall- (n=20) p-value

73 Temporal pole: middle temporal gyrus R 0.210 (0.056) 0.244 (0.059) .141

74 Parahippocampal gyrus R 0.177 (0.061) 0.240 (0.075) .029

75 Anterior cingulate and paracingulate gyri R 0.236 (0.080) 0.276 (0.058) .131

76 Median cingulate and paracingulate gyri R 0.277 (0.079) 0.311 (0.075) .250

77 Posterior cingulate gyrus R 0.201 (0.064) 0.272 (0.082) .024

78 Insula R 0.248 (0.093) 0.287 (0.074) .227

79 Hippocampus L 0.192 (0.072) 0.256 (0.083) .048

80 Hippocampus R 0.182 (0.067) 0.252 (0.080) .024

81 Amygdala L 0.212 (0.062) 0.261 (0.067) .065

82 Amygdala R 0.203 (0.076) 0.254 (0.069) .077

83 Caudate nucleus L 0.239 (0.082) 0.278 (0.062) .157

84 Caudate nucleus R 0.236 (0.080) 0.290 (0.064) .058

85 Lenticular nucleus, putamen L 0.244 (0.081) 0.291 (0.069) .111

86 Lenticular nucleus, putamen R 0.243 (0.088) 0.292 (0.068) .108

87 Lenticular nucleus, pallidum L 0.227 (0.078) 0.277 (0.072) .095

88 Lenticular nucleus, pallidum R 0.234 (0.085) 0.287 (0.068) .076

89 Thalamus L 0.233 (0.071) 0.284 (0.077) .092

90 Thalamus R 0.230 (0.072) 0.281 (0.073) .080

Hall-: Parkinson’s disease patients without hallucinations; Unimodal Hall+: Parkinson’s disease patients with only visual hallucinations

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Table S3: Relative power per AAL region in the gamma band in Parkinson’s disease patients with unimodal hallucinations and patients without hallucinations

AAL region Unimodal Hall+ (n=10)

Hall- (n=20) p-value

1 Gyrus rectus L 0.073 (0.017) 0.091 (0.023) .036

2 Olfactory cortex L 0.054 (0.013) 0.075 (0.017) .002

3 Superior frontal gyrus, orbital part L 0.088 (0.016) 0.108 (0.028) .045

4 Superior frontal gyrus, medial orbital part L 0.088 (0.018) 0.112 (0.026) .013

5 Middle frontal gyrus, orbital part L 0.090 (0.019) 0.116 (0.032) .029

6 Inferior frontal gyrus, orbital part L 0.070 (0.017) 0.100 (0.029) .006

7 Superior frontal gyrus L, dorsolateral 0.090 (0.021) 0.116 (0.024) .007

8 Middle frontal gyrus L 0.087 (0.031) 0.113 (0.024) .017

9 Inferior frontal gyrus, opercular part L 0.068 (0.026) 0.108 (0.045) .016

10 Inferior frontal gyrus, triangular part L 0.077 (0.032) 0.111 (0.030) .008

11 Superior frontal gyrus, medial part L 0.085 (0.024) 0.113 (0.024) .007

12 Supplementary motor area L 0.078 (0.021) 0.103 (0.020) .004

13 Paracentral lobule L 0.083 (0.021) 0.101 (0.019) .024

14 Precentral gyrus L 0.066 (0.020) 0.108 (0.026) .001

15 Rolandic operculum L 0.046 (0.014) 0.080 (0.029) .001

16 Postcentral gyrus L 0.057 (0.020) 0.086 (0.023) .002

17 Superior parietal gyrus L 0.077 (0.024) 0.087 (0.021) .210

18 Inferior parietal gyri L 0.060 (0.019) 0.074 (0.019) .064

19 Supramarginal gyrus L 0.053 (0.019) 0.071 (0.027) .067

20 Angular gyrus L 0.045 (0.012) 0.060 (0.017) .018

21 Precuneus L 0.065 (0.022) 0.080 (0.021) .081

22 Superior occipital gyrus L 0.055 (0.015) 0.063 (0.019) .298

23 Middle occipital gyrus L 0.045 (0.017) 0.054 (0.019) .248

24 Inferior occipital gyrus L 0.046 (0.019) 0.049 (0.024) .765

0.043 (0.011) 0.049 (0.017) .284

26 Cuneus L 0.046 (0.014) 0.060 (0.017) .033

27 Lingual gyrus L 0.043 (0.013) 0.048 (0.019) .428

28 Fusiform gyrus L 0.041 (0.014) 0.054 (0.018) .058

29 Heschl gyrus L 0.043 (0.013) 0.065 (0.019) .003

30 Superior temporal gyrus L 0.049 (0.033) 0.070 (0.025) .064

31 Middle temporal gyrus L 0.043 (0.018) 0.066 (0.041) .113

32 Inferior temporal gyrus L 0.055 (0.017) 0.072 (0.035) .147

33 Temporal pole: superior temporal gyrus L 0.063 (0.018) 0.093 (0.035) .016

34 Temporal pole: middle temporal gyrus L 0.069 (0.019) 0.096 (0.031) .017

35 Parahippocampal gyrus L 0.051 (0.013) 0.071 (0.029) .017

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Table S3: Continued

AAL region Unimodal Hall+ (n=10)

Hall- (n=20) p-value

36 Anterior cingulate and paracingulate gyri L 0.070 (0.023) 0.094 (0.017) .003

37 Median cingulate and paracingulate gyri L 0.057 (0.020) 0.074 (0.017) .025

38 Posterior cingulate gyrus L 0.050 (0.017) 0.061 (0.018) .116

39 Insula L 0.059 (0.022) 0.092 (0.037) .015

40 Gyrus rectus R 0.071 (0.017) 0.087 (0.021) .043

41 Olfactory cortex R 0.055 (0.014) 0.074 (0.020) .011

42 Superior frontal gyrus, orbital part R 0.082 (0.016) 0.102 (0.022) .014

43 Superior frontal gyrus, medial orbital part R 0.083 (0.020) 0.108 (0.027) .014

44 Middle frontal gyrus, orbital part R 0.088 (0.020) 0.111 (0.028) .026

45 Inferior frontal gyrus, orbital part R 0.075 (0.017) 0.104 (0.038) .028

46 Superior frontal gyrus R, dorsolateral 0.087 (0.022) 0.111 (0.025) .014

47 Middle frontal gyrus R 0.084 (0.024) 0.113 (0.030) .011

48 Inferior frontal gyrus, opercular part R 0.063 (0.020) 0.102 (0.044) .013

49 Inferior frontal gyrus, triangular part R 0.075 (0.021) 0.116 (0.052) .025

50 Superior frontal gyrus, medial part R 0.089 (0.023) 0.114 (0.025) .013

51 Supplementary motor area R 0.082 (0.018) 0.102 (0.019) .012

52 Paracentral lobule R 0.078 (0.023) 0.102 (0.020) .007

53 Precentral gyrus R 0.065 (0.019) 0.095 (0.028) .005

54 Rolandic operculum R 0.051 (0.017) 0.090 (0.067) .084

55 Postcentral gyrus R 0.062 (0.028) 0.080 (0.024) .071

56 Superior parietal gyrus R 0.072 (0.028) 0.087 (0.029) .188

57 Inferior parietal gyri R 0.053 (0.018) 0.071 (0.022) .031

58 Supramarginal gyrus R 0.051 (0.021) 0.071 (0.026) .046

59 Angular gyrus R 0.050 (0.016) 0.063 (0.021) .097

60 Precuneus R 0.059 (0.023) 0.073 (0.022) .130

61 Superior occipital gyrus R 0.052 (0.013) 0.061 (0.021) .241

62 Middle occipital gyrus R 0.046 (0.014) 0.059 (0.024) .130

63 Inferior occipital gyrus R 0.056 (0.018) 0.064 (0.029) .465

0.041 (0.013) 0.048 (0.021) .372

65 Cuneus R 0.050 (0.018) 0.055 (0.017) .500

66 Lingual gyrus R 0.039 (0.013) 0.050 (0.022) .132

67 Fusiform gyrus R 0.049 (0.019) 0.060 (0.023) .187

68 Heschl gyrus R 0.043 (0.013) 0.073 (0.054) .088

69 Superior temporal gyrus R 0.046 (0.015) 0.076 (0.058) .123

70 Middle temporal gyrus R 0.045 (0.017) 0.069 (0.033) .037

71 Inferior temporal gyrus R 0.060 (0.014) 0.081 (0.033) .057

72 Temporal pole: superior temporal gyrus R 0.072 (0.018) 0.092 (0.026) .021

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Table S3: Continued

AAL region Unimodal Hall+ (n=10)

Hall- (n=20) p-value

73 Temporal pole: middle temporal gyrus R 0.076 (0.012) 0.097 (0.027) .007

74 Parahippocampal gyrus R 0.051 (0.014) 0.072 (0.024) .006

75 Anterior cingulate and paracingulate gyri R 0.072 (0.023) 0.095 (0.020) .007

76 Median cingulate and paracingulate gyri R 0.058 (0.018) 0.077 (0.019) .014

77 Posterior cingulate gyrus R 0.046 (0.015) 0.061 (0.018) .039

78 Insula R 0.059 (0.017) 0.089 (0.045) .059

79 Hippocampus L 0.046 (0.016) 0.063 (0.018) .025

80 Hippocampus R 0.048 (0.018) 0.072 (0.030) .026

81 Amygdala L 0.056 (0.016) 0.074 (0.026) .043

82 Amygdala R 0.056 (0.012) 0.074 (0.025) .012

83 Caudate nucleus L 0.056 (0.019) 0.077 (0.019) .007

84 Caudate nucleus R 0.055 (0.018) 0.078 (0.018) .003

85 Lenticular nucleus, putamen L 0.056 (0.020) 0.081 (0.028) .017

86 Lenticular nucleus, putamen R 0.055 (0.014) 0.079 (0.028) .005

87 Lenticular nucleus, pallidum L 0.052 (0.018) 0.073 (0.025) .027

88 Lenticular nucleus, pallidum R 0.053 (0.015) 0.075 (0.023) .006

89 Thalamus L 0.052 (0.018) 0.068 (0.020) .041

90 Thalamus R 0.049 (0.014) 0.068 (0.022) .008

Hall-: Parkinson’s disease patients without hallucinations; Unimodal Hall+: Parkinson’s disease patients with only visual hallucinations

171

MEG-based resting-state brain activity in PD

Table S4: Peak frequency per AAL region in Parkinson’s disease patients with unimodal hallucinations and patients without hallucinations

AAL region Unimodal Hall+ (n=10)

Hall- (n=20) p-value

1 Gyrus rectus L 7.06 (0.85) 7.76 (0.72) .026

2 Olfactory cortex L 7.27 (0.95) 8.06 (0.69) .015

3 Superior frontal gyrus, orbital part L 7.06 (0.87) 7.48 (0.68) .156

4 Superior frontal gyrus, medial orbital part L 6.81 (0.81) 7.29 (0.73) .107

5 Middle frontal gyrus, orbital part L 6.85 (0.96) 7.37 (0.88) .148

6 Inferior frontal gyrus, orbital part L 7.15 (1.06) 7.75 (0.72) .077

7 Superior frontal gyrus L, dorsolateral 7.03 (0.95) 7.22 (0.73) .563

8 Middle frontal gyrus L 7.17 (1.06) 7.29 (0.71) .721

9 Inferior frontal gyrus, opercular part L 7.55 (1.08) 7.83 (0.85) .446

10 Inferior frontal gyrus, triangular part L 7.35 (0.99) 7.83 (0.83) .169

11 Superior frontal gyrus, medial part L 6.84 (0.82) 7.26 (0.77) .181

12 Supplementary motor area L 7.36 (1.12) 7.41 (0.85) .896

13 Paracentral lobule L 7.96 (1.28) 7.64 (0.87) .423

14 Precentral gyrus L 8.21 (1.53) 7.75 (0.75) .388

15 Rolandic operculum L 7.70 (0.94) 8.31 (0.79) .072

16 Postcentral gyrus L 8.56 (1.13) 8.27 (0.92) .446

17 Superior parietal gyrus L 7.49 (1.03) 8.25 (0.91) .050

18 Inferior parietal gyri L 7.98 (1.18) 8.56 (0.89) .144

19 Supramarginal gyrus L 7.86 (0.10) 8.59 (0.79) .036

20 Angular gyrus L 7.51 (1.06) 8.50 (0.91) .012

21 Precuneus L 7.24 (0.95) 8.41 (0.99) .004

22 Superior occipital gyrus L 7.15 (1.07) 8.56 (0.97) .001

23 Middle occipital gyrus L 7.20 (1.03) 8.49 (1.11) .005

24 Inferior occipital gyrus L 7.12 (0.93) 8.24 (1.08) .010

7.24 (1.11) 8.57 (0.99) .002

26 Cuneus L 7.31 (1.14) 8.52 (0.91) .004

27 Lingual gyrus L 7.20 (1.06) 8.42 (0.97) .004

28 Fusiform gyrus L 7.10 (0.99) 8.44 (1.07) .003

29 Heschl gyrus L 7.61 (1.03) 8.52 (0.89) .018

30 Superior temporal gyrus L 7.49 (1.04) 8.60 (0.89) .005

31 Middle temporal gyrus L 7.70 (1.25) 8.66 (0.90) .023

32 Inferior temporal gyrus L 7.41 (0.97) 8.44 (0.96) .010

33 Temporal pole: superior temporal gyrus L 7.37 (1.00) 8.21 (0.67) .011

34 Temporal pole: middle temporal gyrus L 7.05 (0.73) 8.09 (0.74) .001

35 Parahippocampal gyrus L 7.34 (1.12) 8.24 (0.91) .025

6

172

Chapter 6

Table S4: Continued

AAL region Unimodal Hall+ (n=10)

Hall- (n=20) p-value

36 Anterior cingulate and paracingulate gyri L 7.05 (0.97) 7.43 (0.88) .284

37 Median cingulate and paracingulate gyri L 7.47 (0.89) 8.02 (0.77) .089

38 Posterior cingulate gyrus L 7.43 (0.97) 8.48 (0.79) .004

39 Insula L 7.47 (0.95) 8.14 (0.81) .056

40 Gyrus rectus R 7.19 (0.86) 7.69 (0.85) .143

41 Olfactory cortex R 7.22 (0.87) 8.01 (0.84) .023

42 Superior frontal gyrus, orbital part R 7.00 (0.91) 7.46 (0.83) .177

43 Superior frontal gyrus, medial orbital part R 6.77 (0.85) 7.35 (0.88) .098

44 Middle frontal gyrus, orbital part R 7.07 (0.79) 7.28 (0.82) .519

45 Inferior frontal gyrus, orbital part R 7.35 (0.78) 7.63 (0.79) .384

46 Superior frontal gyrus R, dorsolateral 7.25 (1.42) 7.34 (0.82) .814

47 Middle frontal gyrus R 7.20 (1.21) 7.27 (0.96) .857

48 Inferior frontal gyrus, opercular part R 7.70 (1.04) 7.90 (0.81) .563

49 Inferior frontal gyrus, triangular part R 7.30 (0.73) 7.82 (0.91) .132

50 Superior frontal gyrus, medial part R 6.88 (0.76) 7.23 (0.82) .279

51 Supplementary motor area R 7.60 (1.17) 7.59 (0.88) .979

52 Paracentral lobule R 7.83 (1.14) 7.96 (0.92) .751

53 Precentral gyrus R 7.90 (1.07) 8.14 (0.93) .523

54 Rolandic operculum R 7.45 (1.03) 8.46 (0.85) .008

55 Postcentral gyrus R 8.08 (1.13) 8.58 (1.08) .248

56 Superior parietal gyrus R 7.23 (0.89) 8.26 (0.94) .007

57 Inferior parietal gyri R 7.67 (1.36) 8.71 (1.00) .024

58 Supramarginal gyrus R 7.45 (1.06) 8.63 (0.87) .003

59 Angular gyrus R 7.14 (1.11) 8.64 (1.02) .001

60 Precuneus R 7.30 (0.89) 8.33 (0.96) .009

61 Superior occipital gyrus R 6.98 (1.03) 8.42 (1.06) .001

62 Middle occipital gyrus R 6.88 (1.01) 8.37 (1.01) .001

63 Inferior occipital gyrus R 6.86 (1.06) 8.29 (1.06) .002

7.12 (1.13) 8.53 (1.00) .002

65 Cuneus R 7.02 (1.05) 8.60 (1.02) .000

66 Lingual gyrus R 6.98 (1.07) 8.47 (1.02) .001

67 Fusiform gyrus R 7.06 (0.95) 8.42 (1.06) .002

68 Heschl gyrus R 7.37 (0.92) 8.74 (0.91) .001

69 Superior temporal gyrus R 7.42 (1.03) 8.78 (0.97) .001

70 Middle temporal gyrus R 7.10 (0.95) 8.66 (1.03) .000

71 Inferior temporal gyrus R 7.16 (1.04) 8.58 (0.94) .001

72 Temporal pole: superior temporal gyrus R 7.02 (0.76) 8.29 (0.85) .000

173

MEG-based resting-state brain activity in PD

Table S4: Continued

AAL region Unimodal Hall+ (n=10)

Hall- (n=20) p-value

73 Temporal pole: middle temporal gyrus R 7.08 (0.94) 8.07 (0.69) .003

74 Parahippocampal gyrus R 7.23 (1.08) 8.18 (0.89) .016

75 Anterior cingulate and paracingulate gyri R 7.01 (0.88) 7.44 (0.78) .182

76 Median cingulate and paracingulate gyri R 7.67 (1.15) 8.07 (0.93) .310

77 Posterior cingulate gyrus R 7.42 (1.03) 8.48 (0.76) .004

78 Insula R 7.27 (1.03) 8.19 (0.85) .014

79 Hippocampus L 7.22 (0.90) 8.31 (0.84) .003

80 Hippocampus R 7.19 (0.86) 8.49 (0.86) .001

81 Amygdala L 7.30 (1.02) 8.24 (0.74) .007

82 Amygdala R 7.22 (1.16) 8.20 (0.87) .015

83 Caudate nucleus L 7.33 (0.98) 7.98 (0.79) .058

84 Caudate nucleus R 7.12 (0.96) 7.93 (0.74) .016

85 Lenticular nucleus, putamen L 7.40 (0.85) 8.08 (0.83) .046

86 Lenticular nucleus, putamen R 7.12 (1.05) 8.23 (0.75) .002

87 Lenticular nucleus, pallidum L 7.43 (0.87) 8.10 (0.81) .048

88 Lenticular nucleus, pallidum R 7.11 (1.03) 8.21 (0.66) .001

89 Thalamus L 7.32 (1.00) 8.17 (0.87) .023

90 Thalamus R 7.36 (0.92) 8.41 (0.88) .005

Hall-: Parkinson’s disease patients without hallucinations; Unimodal Hall+: Parkinson’s disease patients with only visual hallucinations

6

174

Chapter 6

Tab

le S

5: M

ean

rela

tive

pow

er/p

eak

freq

uenc

y pe

r br

ain

regi

on

Hal

l- (

N=2

0)U

nim

odal

Hal

l+ (

N=1

0)M

ulti

mod

al H

all+

(N

=10)

Reg

ion

per

freq

uenc

y ba

ndM

ean

SD

Mea

nS

DM

ean

SD

Fron

tal L

eft

thet

a.1

67.0

38.2

08.0

47.1

49.0

58

Fron

tal L

eft

beta

.282

.048

.253

.068

.314

.096

Fron

tal L

eft

gam

ma

.105

.022

.079

.019

.106

.019

Fron

tal L

eft

PF7.

55.6

587.

19.8

698.

023

.794

Fron

tal R

ight

the

ta.1

61.0

35.2

03.0

45.1

48.0

61

Fron

tal R

ight

bet

a.2

85.0

50.2

56.0

74.3

11.1

03

Fron

tal R

ight

gam

ma

.104

.023

.078

.017

.104

.016

Fron

tal R

ight

PF

7.58

.741

7.26

.813

8.12

1.8

25

Cen

tral

Lef

t th

eta

.164

.045

.211

.060

.150

.088

Cen

tral

Lef

t be

ta.3

32.0

59.2

98.0

82.3

67.1

37

Cen

tral

Lef

t ga

mm

a.0

89.0

24.0

56.0

17.0

87.0

31

Cen

tral

Lef

t PF

8.11

.724

8.16

1.10

78.

79.9

32

Cen

tral

Rig

ht t

heta

.162

.061

.222

.048

0.1

51.0

93

Cen

tral

Rig

ht b

eta

.338

.075

.272

.073

.368

.123

Cen

tral

Rig

ht g

amm

a.0

88.0

35.0

59.0

19.0

84.0

23

Cen

tral

Rig

ht P

F8.

39.8

417.

811.

006

9.16

1.04

4

Pari

etal

Lef

t th

eta

.184

.068

.249

.064

.168

.112

Pari

etal

Lef

t be

ta.3

04.0

92.2

17.0

61.3

18.1

36

Pari

etal

Lef

t ga

mm

a.0

75.0

17.0

60.0

17.0

71.0

22

Pari

etal

Lef

t PF

8.46

.778

7.61

.991

9.09

1.26

1

175

MEG-based resting-state brain activity in PD

Tabl

e S5

: Con

tinue

d

Hal

l- (

N=2

0)U

nim

odal

Hal

l+ (

N=1

0)M

ulti

mod

al H

all+

(N

=10)

Reg

ion

per

freq

uenc

y ba

ndM

ean

SD

Mea

nS

DM

ean

SD

Pari

etal

Rig

ht t

heta

.178

.067

.276

.077

.166

.104

Pari

etal

Rig

ht b

eta

.295

.093

.193

.060

.313

.128

Pari

etal

Rig

ht g

amm

a.0

73.0

21.0

57.0

19.0

69.0

187

Pari

etal

Rig

ht P

F8.

51.8

907.

361.

004

9.12

1.28

6

Occ

ipita

l Lef

t th

eta

.221

.085

.296

.078

.190

.103

Occ

ipit

al L

eft

beta

.228

.097

.145

.047

.234

.094

Occ

ipita

l Lef

t ga

mm

a.0

54.0

17.0

46.0

13.0

50.0

12

Occ

ipita

l Lef

t PF

8.46

.941

7.19

1.01

88.

931.

30

Occ

ipit

al R

ight

the

ta.2

12.0

79.2

96.0

77.1

91.0

98

Occ

ipit

al R

ight

bet

a.2

29.0

93.1

46.0

53.2

28.0

87

Occ

ipita

l Rig

ht g

amm

a.0

57.0

20.0

48.0

13.0

54.0

16

Occ

ipita

l Rig

ht P

F8.

44.9

766.

981.

015

8.85

1.32

2

Tem

pora

l Lef

t th

eta

.197

.082

.276

.078

.178

.101

Tem

pora

l Lef

t be

ta.2

72.0

86.1

99.0

68.2

85.1

00

Tem

pora

l Lef

t ga

mm

a.0

68.0

27.0

47.0

19.0

70.0

34

Tem

pora

l Lef

t PF

8.55

.872

7.55

1.03

28.

981.

223

Tem

pora

l Rig

ht t

heta

.189

.086

.300

.084

.187

.104

Tem

pora

l Rig

ht b

eta

.264

.093

.175

.055

.259

.088

Tem

pora

l Rig

ht g

amm

a.0

75.0

43.0

48.0

11.0

68.0

30

Tem

pora

l Rig

ht P

F8.

69.9

237.

26.9

588.

921.

259

6

176

Chapter 6

Tabl

e S5

: Con

tinue

d

Hal

l- (

N=2

0)U

nim

odal

Hal

l+ (

N=1

0)M

ulti

mod

al H

all+

(N

=10)

Reg

ion

per

freq

uenc

y ba

ndM

ean

SD

Mea

nS

DM

ean

SD

Lim

bic

Left

the

ta.1

92.0

55.2

55.0

55.1

73.0

80

Lim

bic

Left

bet

a.2

66.0

61.2

16.0

63.2

82.0

98

Lim

bic

Left

gam

ma

.079

.021

.058

.015

.076

.022

Lim

bic

Left

PF

8.11

.670

7.27

.886

8.67

1.00

8

Lim

bic

Rig

ht t

heta

.183

.054

.252

.055

.167

.079

Lim

bic

Rig

ht b

eta

.265

.064

.215

.063

.285

.098

Lim

bic

Rig

ht g

amm

a.0

81.0

20.0

61.0

12.0

82.0

28

Lim

bic

Rig

ht P

F8.

15.7

167.

23.8

508.

641.

022

Subc

ortic

al L

eft

thet

a.1

94.0

58.2

53.0

58.1

69.0

87

Subc

ortic

al L

eft

beta

.278

.067

.231

.073

.307

.112

Subc

ortic

al L

eft

gam

ma

.075

.022

.054

.016

.078

.031

Subc

ortic

al L

eft

PF8.

11.7

457.

35.9

138.

711.

057

Subc

ortic

al R

ight

the

ta.1

87.0

53.2

55.0

57.1

72.0

88

Subc

ortic

al R

ight

bet

a.2

81.0

66.2

29.0

78.3

01.11

0

Subc

ortic

al R

ight

gam

ma

.075

.022

.054

.014

.077

.028

Subc

ortic

al R

ight

PF

8.19

.726

7.18

.989

8.72

1.15

6

Hal

l-: P

arki

nson

’s di

seas

e pa

tient

s w

ithou

t hal

luci

natio

ns; M

ultim

odal

Hal

l+: P

arki

nson

’s di

seas

e pa

tient

s w

ith m

ultim

odal

hal

luci

natio

ns; P

F: p

eak

freq

uenc

y; S

D: s

tand

ard

devi

atio

n; U

nim

odal

Hal

l+: P

arki

nson

’s di

seas

e pa

tient

s w

ith o

nly

visu

al h

allu

cina

tions

177

MEG-based resting-state brain activity in PD

Tab

le S

6: R

esul

ts r

egio

n by

freq

uenc

y ba

nd b

y gr

oup

anal

ysis

mea

n di

ffer

ence

Reg

ion

Freq

uenc

y ba

ndG

roup

Gro

upM

ean

diff

eren

ceS

Ep-

valu

eL

ower

bou

ndU

pper

bou

nd

Fron

tal l

eft

The

taC

ontr

olU

nim

odal

-.040

.018

.028

-.076

-.005

mul

timod

al.0

18.0

18.3

19-.0

18.0

54

Uni

mod

alm

ultim

odal

.058

.020

.007

.017

.100

Beta

Con

trol

Uni

mod

al.0

29.0

26.2

75-.0

24.0

82

mul

timod

al-.0

32.0

26.2

28-.0

85.0

21

Uni

mod

alm

ultim

odal

-.061

.030

.051

-.122

.000

Gam

ma

Con

trol

Uni

mod

al.0

26.0

08.0

03.0

09.0

42

mul

timod

al-.0

01.0

08.9

44-.0

17.0

16

Uni

mod

alm

ultim

odal

-.026

.009

.008

-.045

-.007

Peak

freq

uenc

yC

ontr

olU

nim

odal

.364

.290

.217

-.223

.951

mul

timod

al-.4

71.2

90.11

2-1

.058

.116

Uni

mod

alm

ultim

odal

-.835

.335

.017

-1.5

13-.1

57

Fron

tal r

ight

The

taC

ontr

olU

nim

odal

-.042

.017

.019

-.078

-.007

mul

timod

al.0

12.0

17.4

80-.0

23.0

48

Uni

mod

alm

ultim

odal

.055

.020

.009

.014

.095

Beta

Con

trol

Uni

mod

al.0

29.0

28.3

00-.0

27.0

86

mul

timod

al-.0

26.0

28.3

56-.0

83.0

30

Uni

mod

alm

ultim

odal

-.055

.032

.094

-.121

.010

6

178

Chapter 6

Tabl

e S6

: Con

tinue

d

mea

n di

ffer

ence

Reg

ion

Freq

uenc

y ba

ndG

roup

Gro

upM

ean

diff

eren

ceS

Ep-

valu

eL

ower

bou

ndU

pper

bou

nd

Gam

ma

Con

trol

Uni

mod

al.0

26.0

08.0

02.0

10.0

42

mul

timod

al-.0

01.0

08.9

45-.0

16.0

15

Uni

mod

alm

ultim

odal

-.026

.009

.006

-.045

-.008

Peak

freq

uenc

yC

ontr

olU

nim

odal

.319

.302

.298

-.293

.931

mul

timod

al-.5

42.3

02.0

81-1

.154

.071

Uni

mod

alm

ultim

odal

-.861

.349

.018

-1.5

67-.1

54

Cen

tral

left

The

taC

ontr

olU

nim

odal

-.047

.024

.056

-.096

.001

mul

timod

al.0

13.0

24.5

77-.0

35.0

62

Uni

mod

alm

ultim

odal

.061

.028

.034

.005

.117

Beta

Con

trol

Uni

mod

al.0

35.0

35.3

21-.0

35.1

05

mul

timod

al-.0

34.0

35.3

29-.1

04.0

36

Uni

mod

alm

ultim

odal

-.069

.040

.093

-.150

.012

Gam

ma

Con

trol

Uni

mod

al.0

33.0

10.0

01.0

14.0

52

mul

timod

al.0

02.0

10.8

61-.0

18.0

21

Uni

mod

alm

ultim

odal

-.031

.011

.007

-.053

-.009

Peak

freq

uenc

yC

ontr

olU

nim

odal

-.050

.342

.885

-.742

.643

mul

timod

al-.6

80.3

42.0

54-1

.373

.012

Uni

mod

alm

ultim

odal

-.631

.395

.118

-1.4

30.1

69

179

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Tabl

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tinue

d

mea

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Reg

ion

Freq

uenc

y ba

ndG

roup

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Con

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Uni

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al-.0

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timod

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26.6

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42.0

64

Uni

mod

alm

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.072

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.133

Beta

Con

trol

Uni

mod

al.0

66.0

34.0

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36

mul

timod

al-.0

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99.0

41

Uni

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alm

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-.095

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-.176

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Gam

ma

Con

trol

Uni

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al.0

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52

mul

timod

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11.7

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19.0

27

Uni

mod

alm

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-.025

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Peak

freq

uenc

yC

ontr

olU

nim

odal

.584

.362

.115

-.150

1.31

8

mul

timod

al-.7

68.3

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.502

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Uni

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alm

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18.0

03-2

.200

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Pari

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left

The

taC

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timod

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Uni

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alm

ultim

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.153

Beta

Con

trol

Uni

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al.0

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64

mul

timod

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92.0

63

Uni

mod

alm

ultim

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-.101

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.028

-.190

-.011

6

180

Chapter 6

Tabl

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: Con

tinue

d

mea

n di

ffer

ence

Reg

ion

Freq

uenc

y ba

ndG

roup

Gro

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19

Uni

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alm

ultim

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-.011

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.209

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Peak

freq

uenc

yC

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nim

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.846

.375

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1.60

6

mul

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Uni

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Pari

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Con

trol

Uni

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Uni

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.182

Beta

Con

trol

Uni

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58

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Con

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alm

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Peak

freq

uenc

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1.15

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961

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.419

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Uni

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-1.7

68.4

59.0

00-2

.698

-.837

181

MEG-based resting-state brain activity in PD

Tabl

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: Con

tinue

d

mea

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ence

Reg

ion

Freq

uenc

y ba

ndG

roup

Gro

upM

ean

diff

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Occ

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Con

trol

Uni

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al-.0

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01

Uni

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.105

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Beta

Con

trol

Uni

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al.0

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Con

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16

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Peak

freq

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yC

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1.27

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432.

103

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Occ

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Con

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Uni

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Con

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Uni

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6

182

Chapter 6

Tabl

e S6

: Con

tinue

d

mea

n di

ffer

ence

Reg

ion

Freq

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17

Uni

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alm

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-.006

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Peak

freq

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1.45

9.4

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01.6

122.

306

mul

timod

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Uni

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Tem

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Con

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Uni

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80.0

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12

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Uni

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Beta

Con

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Con

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Uni

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Peak

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.999

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1.78

9

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90.2

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Uni

mod

alm

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-1.4

27.4

50.0

03-2

.339

-.515

183

MEG-based resting-state brain activity in PD

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d

mea

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ence

Reg

ion

Freq

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y ba

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36

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Uni

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.108

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Beta

Con

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Uni

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Con

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54

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13.5

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20.0

35

Uni

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alm

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-.019

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.221

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Peak

freq

uenc

yC

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olU

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1.42

7.3

96.0

01.6

242.

229

mul

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34.3

96.5

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Uni

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Lim

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The

taC

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-.062

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68

Uni

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Con

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Uni

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mul

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Uni

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-.067

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6

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Chapter 6

Tabl

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: Con

tinue

d

mea

n di

ffer

ence

Reg

ion

Freq

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36

mul

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13.0

18

Uni

mod

alm

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-.018

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Peak

freq

uenc

yC

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.838

.317

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.196

1.47

9

mul

timod

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60.3

17.0

85-1

.202

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Uni

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alm

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.139

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Lim

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Con

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Uni

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al-.0

69.0

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21

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64

Uni

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Beta

Con

trol

Uni

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Uni

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Con

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Uni

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al.0

20.0

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37

mul

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17.0

15

Uni

mod

alm

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-.021

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Peak

freq

uenc

yC

ontr

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nim

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.914

.323

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.261

1.56

8

mul

timod

al-.4

98.3

23.1

31-1

.151

.156

Uni

mod

alm

ultim

odal

-1.4

12.3

72.0

01-2

.167

-.658

185

MEG-based resting-state brain activity in PD

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d

mea

n di

ffer

ence

Reg

ion

Freq

uenc

y ba

ndG

roup

Gro

upM

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diff

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Con

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Uni

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al-.0

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07

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77

Uni

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Con

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Uni

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1

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Uni

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Gam

ma

Con

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Uni

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al.0

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39

mul

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09.7

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22.0

15

Uni

mod

alm

ultim

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-.023

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Peak

freq

uenc

yC

ontr

olU

nim

odal

.759

.338

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1.44

3

mul

timod

al-.5

99.3

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84-1

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Uni

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.148

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Sub

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ical

ri

ght

The

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Uni

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Con

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Uni

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6

186

Chapter 6

Tabl

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: Con

tinue

d

mea

n di

ffer

ence

Reg

ion

Freq

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Con

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mul

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15

Uni

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Peak

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1.00

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724

mul

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Uni

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Con

trol

: Par

kins

on’s

dise

ase

patie

nts

with

out

hallu

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; Mul

timod

al H

all+

: Par

kins

on’s

dise

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patie

nts

with

mul

timod

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allu

cina

tions

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sta

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Hal

l+: P

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allu

cina

tions

187

MEG-based resting-state brain activity in PD

Table S7: Relative power per AAL region in the theta band in Parkinson’s disease patients with unimodal and multimodal hallucinations

AAL region Unimodal Hall+ (N=10)

Multimodal Hall+ (N=10)

p-value

1 Gyrus rectus L 0.211 (0.046) 0.151 (0.061) .029

2 Olfactory cortex L 0.241 (0.054) 0.159 (0.074) .015

3 Superior frontal gyrus, orbital part L 0.201 (0.051) 0.147 (0.054) .035

4 Superior frontal gyrus, medial orbital part L 0.206 (0.052) 0.145 (0.043) .007

5 Middle frontal gyrus, orbital part L 0.189 (0.055) 0.141 (0.053) .143

6 Inferior frontal gyrus, orbital part L 0.206 (0.051) 0.149 (0.064) .023

7 Superior frontal gyrus L, dorsolateral 0.208 (0.044) 0.149 (0.052) .007

8 Middle frontal gyrus L 0.206 (0.057) 0.144 (0.056) .035

9 Inferior frontal gyrus, opercular part L 0.212 (0.062) 0.149 (0.073) .075

10 Inferior frontal gyrus, triangular part L 0.206 (0.059) 0.140 (0.052) .019

11 Superior frontal gyrus, medial part L 0.222 (0.047) 0.155 (0.047) .009

12 Supplementary motor area L 0.211 (0.052) 0.161 (0.071) .075

13 Paracentral lobule L 0.181 (0.054) 0.152 (0.077) .123

14 Precentral gyrus L 0.195 (0.060) 0.150 (0.078) .089

15 Rolandic operculum L 0.245 (0.065) 0.152 (0.093) .029

16 Postcentral gyrus L 0.194 (0.065) 0.149 (0.094) .043

17 Superior parietal gyrus L 0.232 (0.063) 0.163 (0.104) .029

18 Inferior parietal gyri L 0.232 (0.067) 0.161 (0.121) .052

19 Supramarginal gyrus L 0.247 (0.069) 0.168 (0.116) .035

20 Angular gyrus L 0.285 (0.081) 0.183 (0.123) .029

21 Precuneus L 0.250 (0.064) 0.167 (0.100) .029

22 Superior occipital gyrus L 0.281 (0.078) 0.181 (0.114) .023

23 Middle occipital gyrus L 0.297 (0.080) 0.194 (0.114) .029

24 Inferior occipital gyrus L 0.302 (0.094) 0.201 (0.092) .043

0.291 (0.077) 0.178 (0.095) .009

26 Cuneus L 0.284 (0.078) 0.180 (0.112) .019

27 Lingual gyrus L 0.306 (0.083) 0.181 (0.088) .007

28 Fusiform gyrus L 0.308 (0.087) 0.219 (0.121) .089

29 Heschl gyrus L 0.271 (0.072) 0.158 (0.089) .009

30 Superior temporal gyrus L 0.263 (0.073) 0.163 (0.090) .029

31 Middle temporal gyrus L 0.290 (0.095) 0.196 (0.123) .052

32 Inferior temporal gyrus L 0.281 (0.081) 0.196 (0.112) .052

33 Temporal pole: superior temporal gyrus L 0.236 (0.061) 0.167 (0.081) .063

34 Temporal pole: middle temporal gyrus L 0.234 (0.054) 0.159 (0.070) .019

35 Parahippocampal gyrus L 0.282 (0.071) 0.196 (0.100) .063

6

188

Chapter 6

Table S7: Continued

AAL region Unimodal Hall+ (N=10)

Multimodal Hall+ (N=10)

p-value

36 Anterior cingulate and paracingulate gyri L 0.238 (0.056) 0.156 (0.054) .004

37 Median cingulate and paracingulate gyri L 0.240 (0.059) 0.169 (0.088) .023

38 Posterior cingulate gyrus L 0.269 (0.060) 0.172 (0.093) .029

39 Insula L 0.239 (0.061) 0.158 (0.085) .043

40 Gyrus rectus R 0.210 (0.045) 0.152 (0.060) .015

41 Olfactory cortex R 0.239 (0.053) 0.163 (0.072) .019

42 Superior frontal gyrus, orbital part R 0.196 (0.045) 0.142 (0.048) .019

43 Superior frontal gyrus, medial orbital part R 0.204 (0.048) 0.142 (0.048) .004

44 Middle frontal gyrus, orbital part R 0.184 (0.060) 0.136 (0.042) .075

45 Inferior frontal gyrus, orbital part R 0.200 (0.057) 0.148 (0.058) .089

46 Superior frontal gyrus R, dorsolateral 0.206 (0.045) 0.147 (0.062) .029

47 Middle frontal gyrus R 0.195 (0.048) 0.148 (0.069) .063

48 Inferior frontal gyrus, opercular part R 0.200 (0.049) 0.149 (0.082) .063

49 Inferior frontal gyrus, triangular part R 0.204 (0.056) 0.150 (0.073) .063

50 Superior frontal gyrus, medial part R 0.216 (0.049) 0.144 (0.043) .003

51 Supplementary motor area R 0.201 (0.046) 0.155 (0.074) .035

52 Paracentral lobule R 0.186 (0.055) 0.152 (0.081) .052

53 Precentral gyrus R 0.195 (0.036) 0.149 (0.088) .015

54 Rolandic operculum R 0.259 (0.066) 0.159 (0.096) .011

55 Postcentral gyrus R 0.213 (0.054) 0.144 (0.096) .011

56 Superior parietal gyrus R 0.251 (0.067) 0.160 (0.102) .015

57 Inferior parietal gyri R 0.264 (0.086) 0.154 (0.102) .015

58 Supramarginal gyrus R 0.283 (0.080) 0.169 (0.126) .011

59 Angular gyrus R 0.298 (0.090) 0.181 (0.105) .029

60 Precuneus R 0.283 (0.083) 0.164 (0.094) .007

61 Superior occipital gyrus R 0.291 (0.076) 0.184 (0.095) .015

62 Middle occipital gyrus R 0.313 (0.093) 0.208 (0.105) .029

63 Inferior occipital gyrus R 0.294 (0.081) 0.196 (0.096) .019

0.297 (0.079) 0.183 (0.099) .015

65 Cuneus R 0.291 (0.076) 0.172 (0.101) .009

66 Lingual gyrus R 0.300 (0.077) 0.189 (0.101) .019

67 Fusiform gyrus R 0.287 (0.078) 0.204 (0.104) .063

68 Heschl gyrus R 0.292 (0.071) 0.179 (0.109) .011

69 Superior temporal gyrus R 0.305 (0.092) 0.175 (0.105) .009

70 Middle temporal gyrus R 0.315 (0.109) 0.206 (0.121) .023

71 Inferior temporal gyrus R 0.271 (0.075) 0.190 (0.089) .052

72 Temporal pole: superior temporal gyrus R 0.230 (0.056) 0.161 (0.085) .043

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Table S7: Continued

AAL region Unimodal Hall+ (N=10)

Multimodal Hall+ (N=10)

p-value

73 Temporal pole: middle temporal gyrus R 0.230 (0.055) 0.155 (0.066) .009

74 Parahippocampal gyrus R 0.274 (0.070) 0.184 (0.093) .029

75 Anterior cingulate and paracingulate gyri R 0.229 (0.057) 0.150 (0.054) .007

76 Median cingulate and paracingulate gyri R 0.229 (0.054) 0.164 (0.085) .019

77 Posterior cingulate gyrus R 0.281 (0.067) 0.170 (0.089) .007

78 Insula R 0.244 (0.068) 0.162 (0.086) .029

79 Hippocampus L 0.282 (0.067) 0.191 (0.099) .075

80 Hippocampus R 0.287 (0.071) 0.183 (0.097) .035

81 Amygdala L 0.262 (0.069) 0.184 (0.094) .063

82 Amygdala R 0.259 (0.064) 0.175 (0.086) .043

83 Caudate nucleus L 0.241 (0.052) 0.159 (0.075) .019

84 Caudate nucleus R 0.247 (0.052) 0.164 (0.076) .015

85 Lenticular nucleus, putamen L 0.248 (0.060) 0.163 (0.087) .019

86 Lenticular nucleus, putamen R 0.250 (0.064) 0.169 (0.090) .043

87 Lenticular nucleus, pallidum L 0.264 (0.067) 0.168 (0.089) .015

88 Lenticular nucleus, pallidum R 0.256 (0.063) 0.171 (0.089) .023

89 Thalamus L 0.251 (0.057) 0.171 (0.105) .019

90 Thalamus R 0.261 (0.053) 0.183 (0.105) .035

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Table S8: Relative power per AAL region in the gamma band in Parkinson’s disease patients with unimodal and multimodal hallucinations

AAL region Unimodal Hall+ (N=10)

Multimodal Hall+ (N=10)

p-value

1 Gyrus rectus L 0.073 (0.017) 0.092 (0.021) .043

2 Olfactory cortex L 0.054 (0.013) 0.071 (0.019) .052

3 Superior frontal gyrus, orbital part L 0.088 (0.016) 0.115 (0.020) .004

4 Superior frontal gyrus, medial orbital part L 0.088 (0.018) 0.117 (0.020) .003

5 Middle frontal gyrus, orbital part L 0.090 (0.019) 0.124 (0.021) .004

6 Inferior frontal gyrus, orbital part L 0.070 (0.017) 0.100 (0.026) .011

7 Superior frontal gyrus L, dorsolateral 0.090 (0.021) 0.115 (0.021) .023

8 Middle frontal gyrus L 0.087 (0.031) 0.114 (0.022) .043

9 Inferior frontal gyrus, opercular part L 0.068 (0.026) 0.107 (0.044) .023

10 Inferior frontal gyrus, triangular part L 0.077 (0.032) 0.109 (0.026) .015

11 Superior frontal gyrus, medial part L 0.085 (0.024) 0.114 (0.015) .007

12 Supplementary motor area L 0.078 (0.021) 0.098 (0.020) .075

13 Paracentral lobule L 0.083 (0.021) 0.097 (0.022) .165

14 Precentral gyrus L 0.066 (0.020) 0.090 (0.021) .029

15 Rolandic operculum L 0.046 (0.014) 0.095 (0.070) .011

16 Postcentral gyrus L 0.057 (0.020) 0.077 (0.022) .029

17 Superior parietal gyrus L 0.077 (0.024) 0.080 (0.027) .739

18 Inferior parietal gyri L 0.060 (0.019) 0.066 (0.026) .529

19 Supramarginal gyrus L 0.053 (0.019) 0.076 (0.036) .165

20 Angular gyrus L 0.045 (0.012) 0.059 (0.018) .105

21 Precuneus L 0.065 (0.022) 0.072 (0.025) .436

22 Superior occipital gyrus L 0.055 (0.015) 0.059 (0.015) .684

23 Middle occipital gyrus L 0.045 (0.017) 0.048 (0.016) .796

24 Inferior occipital gyrus L 0.046 (0.019) 0.047 (0.011) .971

0.043 (0.011) 0.044 (0.017) .796

26 Cuneus L 0.046 (0.014) 0.055 (0.018) .280

27 Lingual gyrus L 0.043 (0.013) 0.047 (0.015) .529

28 Fusiform gyrus L 0.041 (0.014) 0.048 (0.011) .393

29 Heschl gyrus L 0.043 (0.013) 0.075 (0.048) .035

30 Superior temporal gyrus L 0.049 (0.033) 0.076 (0.047) .105

31 Middle temporal gyrus L 0.043 (0.018) 0.064 (0.026) .035

32 Inferior temporal gyrus L 0.054 (0.017) 0.067 (0.018) .143

33 Temporal pole: superior temporal gyrus L 0.063 (0.018) 0.093 (0.036) .023

34 Temporal pole: middle temporal gyrus L 0.069 (0.019) 0.094 (0.032) .019

35 Parahippocampal gyrus L 0.051 (0.013) 0.065 (0.031) .481

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Table S8: Continued

AAL region Unimodal Hall+ (N=10)

Multimodal Hall+ (N=10)

p-value

36 Anterior cingulate and paracingulate gyri L 0.070 (0.023) 0.094 (0.015) .019

37 Median cingulate and paracingulate gyri L 0.057 (0.021) 0.071 (0.016) .089

38 Posterior cingulate gyrus L 0.050 (0.017) 0.055 (0.019) .529

39 Insula L 0.059 (0.022) 0.095 (0.044) .023

40 Gyrus rectus R 0.071 (0.017) 0.092 (0.022) .023

41 Olfactory cortex R 0.055 (0.014) 0.075 (0.019) .015

42 Superior frontal gyrus, orbital part R 0.082 (0.016) 0.110 (0.024) .003

43 Superior frontal gyrus, medial orbital part R 0.083 (0.020) 0.114 (0.026) .007

44 Middle frontal gyrus, orbital part R 0.088 (0.020) 0.114 (0.021) .015

45 Inferior frontal gyrus, orbital part R 0.075 (0.017) 0.102 (0.016) .001

46 Superior frontal gyrus R, dorsolateral 0.087 (0.022) 0.109 (0.018) .089

47 Middle frontal gyrus R 0.084 (0.024) 0.113 (0.022) .023

48 Inferior frontal gyrus, opercular part R 0.063 (0.020) 0.101 (0.035) .005

49 Inferior frontal gyrus, triangular part R 0.075 (0.021) 0.106 (0.022) .009

50 Superior frontal gyrus, medial part R 0.089 (0.023) 0.118 (0.017) .004

51 Supplementary motor area R 0.082 (0.018) 0.100 (0.017) .035

52 Paracentral lobule R 0.078 (0.023) 0.101 (0.025) .052

53 Precentral gyrus R 0.065 (0.019) 0.091 (0.020) .009

54 Rolandic operculum R 0.051 (0.017) 0.087 (0.036) .019

55 Postcentral gyrus R 0.062 (0.028) 0.075 (0.021) .280

56 Superior parietal gyrus R 0.072 (0.028) 0.079 (0.024) .529

57 Inferior parietal gyri R 0.053 (0.018) 0.065 (0.018) .089

58 Supramarginal gyrus R 0.051 (0.021) 0.074 (0.026) .075

59 Angular gyrus R 0.050 (0.016) 0.061 (0.016) .105

60 Precuneus R 0.059 (0.023) 0.068 (0.022) .529

61 Superior occipital gyrus R 0.052 (0.013) 0.061 (0.014) .247

62 Middle occipital gyrus R 0.046 (0.014) 0.053 (0.014) .579

63 Inferior occipital gyrus R 0.056 (0.018) 0.056 (0.024) .912

0.041 (0.013) 0.046 (0.017) .631

65 Cuneus R 0.050 (0.018) 0.055 (0.016) .739

66 Lingual gyrus R 0.039 (0.013) 0.048 (0.018) .280

67 Fusiform gyrus R 0.049 (0.019) 0.058 (0.024) .481

68 Heschl gyrus R 0.043 (0.013) 0.064 (0.036) .105

69 Superior temporal gyrus R 0.046 (0.015) 0.070 (0.036) .063

70 Middle temporal gyrus R 0.045 (0.017) 0.062 (0.030) .165

71 Inferior temporal gyrus R 0.060 (0.014) 0.073 (0.023) .247

72 Temporal pole: superior temporal gyrus R 0.072 (0.018) 0.101 (0.042) .190

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Table S8: Continued

AAL region Unimodal Hall+ (N=10)

Multimodal Hall+ (N=10)

p-value

73 Temporal pole: middle temporal gyrus R 0.076 (0.012) 0.101 (0.045) .280

74 Parahippocampal gyrus R 0.051 (0.014) 0.070 (0.036) .280

75 Anterior cingulate and paracingulate gyri R 0.072 (0.023) 0.097 (0.016) .015

76 Median cingulate and paracingulate gyri R 0.058 (0.018) 0.080 (0.022) .029

77 Posterior cingulate gyrus R 0.046 (0.015) 0.056 (0.023) .190

78 Insula R 0.059 (0.017) 0.089 (0.033) .063

79 Hippocampus L 0.046 (0.016) 0.062 (0.030) .218

80 Hippocampus R 0.048 (0.018) 0.067 (0.033) .218

81 Amygdala L 0.055 (0.016) 0.080 (0.045) .190

82 Amygdala R 0.056 (0.013) 0.082 (0.043) .190

83 Caudate nucleus L 0.056 (0.019) 0.074 (0.015) .035

84 Caudate nucleus R 0.055 (0.018) 0.075 (0.016) .029

85 Lenticular nucleus, putamen L 0.056 (0.020) 0.084 (0.031) .019

86 Lenticular nucleus, putamen R 0.055 (0.014) 0.080 (0.027) .035

87 Lenticular nucleus, pallidum L 0.052 (0.018) 0.078 (0.033) .035

88 Lenticular nucleus, pallidum R 0.053 (0.015) 0.079 (0.032) .035

89 Thalamus L 0.052 (0.018) 0.072 (0.035) .143

90 Thalamus R 0.049 (0.014) 0.070 (0.030) .165

AAL regions between unimodal Hall+ and multimodal Hall+ groups after FDR-correction for multiple comparisons)Multimodal Hall+: Parkinson’s disease patients with multimodal hallucinations; Unimodal Hall+: Parkinson’s disease patients with only visual hallucinations

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Table S9: Peak frequency per AAL region in Parkinson’s disease patients with unimodal and multimodal hallucinations

AAL region Unimodal Hall+ (N=10)

Multimodal Hall+ (N=10)

p-value

1 Gyrus rectus L 7.06 (0.85) 8.24 (1.12) .015

2 Olfactory cortex L 7.27 (0.95) 8.81 (1.16) .007

3 Superior frontal gyrus, orbital part L 7.06 (0.87) 7.83 (0.95) .052

4 Superior frontal gyrus, medial orbital part L 6.81 (0.81) 7.72 (0.68) .015

5 Middle frontal gyrus, orbital part L 6.85 (0.96) 7.69 (1.04) .075

6 Inferior frontal gyrus, orbital part L 7.15 (1.06) 8.32 (0.92) .029

7 Superior frontal gyrus L, dorsolateral 7.03 (0.95) 7.56 (0.84) .247

8 Middle frontal gyrus L 7.17 (1.06) 7.64 (0.69) .247

9 Inferior frontal gyrus, opercular part L 7.55 (1.08) 8.32 (0.85) .123

10 Inferior frontal gyrus, triangular part L 7.35 (0.99) 8.01 (0.99) .123

11 Superior frontal gyrus, medial part L 6.84 (0.82) 7.61 (0.61) .043

12 Supplementary motor area L 7.36 (1.12) 7.96 (0.76) .190

13 Paracentral lobule L 7.96 (1.28) 8.58 (1.13) .247

14 Precentral gyrus L 8.21 (1.53) 8.50 (1.01) .436

15 Rolandic operculum L 7.70 (0.94) 8.88 (0.97) .035

16 Postcentral gyrus L 8.56 (1.13) 8.98 (1.07) .529

17 Superior parietal gyrus L 7.49 (1.03) 9.07 (1.14) .007

18 Inferior parietal gyri L 7.98 (1.18) 9.19 (1.31) .063

19 Supramarginal gyrus L 7.86 (1.00) 9.01 (1.17) .015

20 Angular gyrus L 7.51 (1.06) 9.05 (1.36) .019

21 Precuneus L 7.24 (0.95) 9.13 (1.49) .007

22 Superior occipital gyrus L 7.15 (1.07) 8.96 (1.51) .009

23 Middle occipital gyrus L 7.20 (1.03) 8.91 (1.21) .005

24 Inferior occipital gyrus L 7.12 (0.93) 8.78 (1.31) .009

7.24 (1.11) 8.04 (1.34) .004

26 Cuneus L 7.31 (1.14) 9.01 (1.43) .015

27 Lingual gyrus L 7.20 (1.06) 8.99 (1.25) .007

28 Fusiform gyrus L 7.10 (0.99) 8.84 (1.29) .009

29 Heschl gyrus L 7.61 (1.03) 9.19 (1.16) .023

30 Superior temporal gyrus L 7.49 (1.04) 8.94 (1.22) .029

31 Middle temporal gyrus L 7.70 (1.25) 8.95 (1.34) .089

32 Inferior temporal gyrus L 7.41 (0.97) 8.85 (1.31) .019

33 Temporal pole: superior temporal gyrus L 7.37 (1.00) 8.46 (0.95) .043

34 Temporal pole: middle temporal gyrus L 7.05 (0.73) 8.54 (0.99) .004

35 Parahippocampal gyrus L 7.34 (1.12) 8.79 (1.24) .043

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Table S9: Continued

AAL region Unimodal Hall+ (N=10)

Multimodal Hall+ (N=10)

p-value

36 Anterior cingulate and paracingulate gyri L 7.05 (0.97) 8.35 (0.84) .009

37 Median cingulate and paracingulate gyri L 7.47 (0.89) 8.76 (1.08) .003

38 Posterior cingulate gyrus L 7.43 (0.97) 0.12 (1.27) .005

39 Insula L 7.47 (0.95) 8.53 (0.83) .029

40 Gyrus rectus R 7.19 (0.86) 8.25 (0.98) .019

41 Olfactory cortex R 7.22 (0.87) 8.71 (1.19) .011

42 Superior frontal gyrus, orbital part R 7.00 (0.91) 7.89 (0.92) .043

43 Superior frontal gyrus, medial orbital part R 6.77 (0.85) 7.80 (0.85) .011

44 Middle frontal gyrus, orbital part R 7.07 (0.79) 7.79 (0.89) .063

45 Inferior frontal gyrus, orbital part R 7.35 (0.78) 8.29 (1.07) .029

46 Superior frontal gyrus R, dorsolateral 7.25 (1.42) 7.83 (0.75) .123

47 Middle frontal gyrus R 7.20 (1.21) 7.91 (0.75) .089

48 Inferior frontal gyrus, opercular part R 7.70 (1.04) 8.74 (1.12) .052

49 Inferior frontal gyrus, triangular part R 7.30 (0.73) 8.11 (0.91) .035

50 Superior frontal gyrus, medial part R 6.88 (0.76) 7.74 (0.69) .023

51 Supplementary motor area R 7.60 (1.17) 8.08 (0.82) .123

52 Paracentral lobule R 7.83 (1.14) 8.44 (1.15) .436

53 Precentral gyrus R 7.90 (1.07) 9.08 (1.09) .035

54 Rolandic operculum R 7.45 (1.03) 9.11 (1.17) .005

55 Postcentral gyrus R 8.08 (1.13) 9.30 (1.15) .029

56 Superior parietal gyrus R 7.23 (0.89) 8.95 (1.45) .009

57 Inferior parietal gyri R 7.67 (1.36) 9.45 (1.43) .009

58 Supramarginal gyrus R 7.45 (1.06) 9.10 (1.28) .009

59 Angular gyrus R 7.14 (1.11) 9.00 (1.28) .005

60 Precuneus R 7.30 (0.89) 9.12 (1.26) .004

61 Superior occipital gyrus R 7.98 (1.03) 8.88 (1.50) .009

62 Middle occipital gyrus R 6.88 (1.01) 8.69 (1.21) .004

63 Inferior occipital gyrus R 6.86 (1.06) 8.76 (1.35) .004

7.12 (1.13) 9.00 (1.35) .009

65 Cuneus R 7.02 (1.05) 9.06 (1.42) .007

66 Lingual gyrus R 6.98 (1.07) 8.88 (1.37) .004

67 Fusiform gyrus R 7.06 (0.95) 8.71 (1.32) .009

68 Heschl gyrus R 7.37 (0.92) 9.02 (1.10) .004

69 Superior temporal gyrus R 7.42 (1.03) 9.10 (1.19) .007

70 Middle temporal gyrus R 7.10 (0.95) 8.77 (1.38) .015

71 Inferior temporal gyrus R 7.16 (1.04) 8.80 (1.42) .015

72 Temporal pole: superior temporal gyrus R 7.02 (0.76) 8.62 (1.04) .003

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Table S9: Continued

AAL region Unimodal Hall+ (N=10)

Multimodal Hall+ (N=10)

p-value

73 Temporal pole: middle temporal gyrus R 7.08 (0.94) 8.62 (0.99) .005

74 Parahippocampal gyrus R 7.23 (1.08) 8.70 (1.28) .011

75 Anterior cingulate and paracingulate gyri R 7.01 (0.88) 8.23 (0.90) .007

76 Median cingulate and paracingulate gyri R 7.67 (1.15) 8.63 (1.00) .063

77 Posterior cingulate gyrus R 7.42 (1.03) 9.04 (1.17) .007

78 Insula R 7.27 (1.03) 8.99 (1.20) .004

79 Hippocampus L 7.22 (0.90) 8.68 (1.20) .015

80 Hippocampus R 7.19 (0.86) 8.67 (1.21) .009

81 Amygdala L 7.30 (1.02) 8.72 (1.16) .019

82 Amygdala R 7.22 (1.16) 8.71 (1.27) .019

83 Caudate nucleus L 7.33 (0.98) 8.51 (1.06) .019

84 Caudate nucleus R 7.12 (0.96) 8.54 (1.10) .007

85 Lenticular nucleus, putamen L 7.40 (0.85) 8.72 (0.93) .007

86 Lenticular nucleus, putamen R 7.12 (1.05) 8.80 (1.31) .009

87 Lenticular nucleus, pallidum L 7.43 (0.87) 8.73 (1.01) .019

88 Lenticular nucleus, pallidum R 7.11 (1.03) 8.78 (1.15) .005

89 Thalamus L 7.32 (1.00) 8.89 (1.27) .015

90 Thalamus R 7.36 (0.92) 8.75 (1.11) .011

Multimodal Hall+: Parkinson’s disease patients with multimodal hallucinations; Unimodal Hall+: Parkinson’s disease patients with only visual hallucinations

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Table S10: Relative power per frequency band and peak frequency, corrected for medication, in Parkinson’s disease patients with unimodal, multimodal, and without hallucinations

Unimodal Hall+vs. Hall-

Multimodal Hall+vs. Hall-

Unimodal Hall+ vs. Multimodal Hall+

Delta F(7,19)=1.37, p=.254 F(7,19)=1.71, p=.203 F(7,11)=1.85, p=.191

Theta F(7,19)=7.77, p=.010 F(7,19)=0.60, p=.448 F(7,11)=5.48, p=.032

Alpha1 F(7,19)=0.22, p=.640 F(7,19)=0.52, p=.480 F(7,11)=1.55, p=.230

Alpha2 F(7,19)=1.16, p=.291 F(7,19)=3.35, p=.079 F(7,11)=3.03, p=.100

Beta F(7,19)=4.68, p=.040 F(7,19)=0.36, p=.555 F(7,11)=2.93, p=.105

Gamma F(7,19)=7.92, p=.009 F(7,19)=0.01, p=.935 F(7,11)=5.82, p=.027

Peak frequency F(7,19)=6.56, p=.017 F(7,19)=3.56, p=.071 F(7,11)=8.77, p=.009

Power is the relative power per frequency band (delta [0.5–4 Hz], theta [4–8 Hz], alpha1 [8–10 Hz], alpha2 [10–13 Hz], beta [13–30 Hz], and gamma [30-48 Hz]), averaged over all 90 AAL regions. Peak frequency is the frequency with highest power in range between 4 and 13 Hz, averaged over all 90 AAL regions.Hall-: Parkinson’s disease patients without hallucinations; Multimodal Hall+: Parkinson’s disease patients with multimodal hallucinations; Unimodal Hall+: Parkinson’s disease patients with only visual hallucinations

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