Comparing brain activation during auditory verbal hallucinations to stimulus detection – a pilot study

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Comparing brain activation during auditory verbal

hallucinations to stimulus detection – a pilot study

Name: Romy Bakker Student number: 5744385

Supervisors: K. Diederen, Dr. & R. van Lutterveld, M.Sc Co-assessor: R. Rouw, Dr.

Msc in Brain and Cognitive Sciences: Cognitive Neuroscience Date: 13-12-2011

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Abstract

Background: Activation in brain areas during auditory verbal hallucinations seems to be

comparable to areas recruited during stimulus detection. However, it is still not examined to what extent these cognitive aspects activate similar areas.

Method: Six patients with a psychotic disorder conducted a simple target detection task and

indicated the presence of auditory verbal hallucinations in one task, during a 3-Tesla functional magnetic resonance imaging scan, by pushing buttons. One sample t-tests were performed to reveal activation during hallucinations and detection of a tone. Additionally, a conjunction analysis was performed to reveal overlapping significantly activated areas.

Results: First level analysis during auditory verbal hallucinations revealed brain activation in

the right inferior and middle frontal gyrus, right inferior parietal lobule, left superior temporal gyrus, bilateral precentral gyrus, right precuneus, right cuneus and cingulate gyrus. Prominent activation during detection was observed in the bilateral inferior frontal gyrus, right middle frontal gyrus, bilateral inferior parietal lobule, bilateral precentral gyrus, left superior temporal gyrus and right precuneus. Conjunction analysis, which shows similar activated areas in both conditions, revealed activation in the left middle temporal gyrus, bilateral inferior parietal lobule, the right precuneus, right inferior and middle frontal gyrus, right posterior cingulate gyrus, left fusiform gyrus and the left precentral gyrus

Conclusions: The conjunction analysis showed that comparable areas are activated during

stimulus detection and auditory verbal hallucinations. This could indicate that while hallucinations are measured, more cognitive functions are engaged, for example detection of a hallucination, which could declare a part of the found activation in hallucinations.

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Introduction

Auditory verbal hallucinations (AVH) are auditory perceptions in the absence of external sources (Jadri et al, 2011) and are a cardinal feature of psychosis (David, 1999). Patients experiencing AVH commonly report hearing words, sentences and conversations that are often intrusive on their thoughts (Jadri et al, 2011). About 70% of schizophrenia patients experience them al least once per month (Sartorius et al., 1986). In 25% of these patients, AVH are drug-resistant, which may leads to chronic presence of this symptom resulting in a decreased quality of life (Shergill et al., 1998).

Several neuroimaging studies investigated brain activation during hallucinations. Most of these studies have reported activation in bilateral auditory and language-related areas during the experience of AVH (Copolov et al., 2003; Diederen et al., 2010; Lennox et al., 2000; Raij et al., 2009; Sommer et al., 2008). Furthermore, activation was also observed in the middle frontal gyrus, medial temporal gyrus and temporoparietal areas.

While activation of these areas is generally considered to result from hallucinations per se, other cognitive functions seemed to rely also on activation in these areas, for example, studies examining stimulus detection reported activation in similar areas (Beck et al., 2001; Hampshire et al., 2010; Hampshire et al., 2007; Hampshire et al., 2008; Hampshire et al., 2009; Kiehl et al., 2001; Muller et al., 2002). In these studies target detection tasks were performed, in which visually displayed targets or auditory targets surrounded by distractors had to be detected (Hampshire et al., 2008, Kiehl et al., 2001).

These findings suggest that studies investigating the state of AVH measure more cognitive aspects than AVH alone. For example, detection of a hallucination or button presses to indicate an AVH could represent a part of the brain activation found during AVH, as these processes are possibly going on during AVH. Comparing brain activation during both AVH and stimulus detection could explain more about the activation found during AVH. Eventually, this could lead to a better target for treatment of AVH in the future.

The present pilot study focused on comparing brain activation during AVH to stimulus detection in schizophrenia patients. Psychotic patients with frequent AVH were exposed to a simple auditory detection task. In addition, they were asked to indicate their own AVH by pushing a button at onset and offset of an AVH. The expectation of this pilot study is that in both task similar areas will be activated, as we expect that part of AVH activation can be explained as activation due to detection. Furthermore, also a prediction of this research include that some areas will be exclusively activated during AVH.

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Methods

Subjects

Ten right-handed patients with a psychotic disorder were included in this study. All subjects used antipsychotic medication during the study, but still experienced AVH. They were recruited from the Department of Psychiatry, University Medical Centre, Utrecht, the Netherlands. Patients were selected on the basis of several inclusion criteria: 1) frequent AVH, 2) frequent moments without AVH, 3) Diagnosis Schizophrenia or Psychosis not otherwise specified. 4) The ability to indicate the onset and offset of their own hallucinations. The study consisted of two different parts; first patients were tested behaviourally outside the scanner using a laptop. Second, participants performed the same task in the MRI scanner. All participants conducted the behavioural part. Four of them were excluded after this part. Three patients experienced continuous AVH and were therefore not able to indicate onset and offset. One patient did not understand the task properly and was therefore excluded. The remaining six patients participated in the fMRI part of the study.

Patients were diagnosed by an independent psychiatrist using the Comprehensive Assessment of Symptoms of History (CASH) according to DSM-IV criteria (Andreasen et al., 1992). On the day of the fMRI scan, the Positive And Negative Syndrome Scale (PANSS) was used for the assessment of symptoms over the last week (Kay et al., 1987). The clinical characteristics of the patients are summarized in Table 1. The study was approved by the Human Ethics Committee of the University Medial Center, Utrecht. After complete information and description of the study to the patients, written informed consent was acquired.

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Table 1. Characteristics of the patients performing both behavioural and fMRI task

Subject Age Gender Handedness Diagnosis Typical

Antipshychotic Medication

Atipical

Antipsychotic medication

A 60 Female Right Psychosis not

otherwise specified

- Quetiapine (50 mg)

B 22 Male Right Schizophrenia - Quetiapine (200 mg, 50 mg)

C 49 Male Right Schizophrenia - Clozapine (300 mg)

Risperidon (4mg)

D 29 Female Right Schizophrenia - Clozapine (250 mg, 50 mg)

E 44 Male Right Schizophrenia - Clozapine (300 mg)

F 30 Female Right Schizophrenia,

paranoid type

Flupentixol (100 mg)

Clozapine (100 mg, 25 mg)

Experimental design

The experiment consisted of a behavioural and an fMRI part. The behavioural part was performed to select and provide training the patients for the fMRI part. Additionally, information about the mean hallucination duration and the number of hallucinations was used for the fMRI part.

In both parts of the study the same task was performed. The task consisted of both an auditory detection task and an indication of hallucinations. The behavioural part was performed behind a laptop. The task started with a training of 1 minute, in which four tones were presented, to enable the participant to get familiar with the tones and button presses. Subsequently, the main task was started, which lasted 20 minutes. Tones of 500 Hz with a jittered duration around 10 seconds were presented through a normal headphone to both ears. At the screen two boxes were presented, shown in figure 1. The instructions were to push the left button ‘Z’ whenever they experienced a hallucination and hold that button until the offset of a hallucination. For detection of tones participants were instructed to push the right button ‘M’ and hold that button until the offset of the tone. These buttons corresponded with the boxes on the screen, which displays ‘push here for voices’ on the left side and ‘push here for tone’ on the right side.

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Figure 1. Experimental setup of the first part. The boxes in the enlargement of the

laptopscreen say ‘push here for voices’ on the left side and ‘push here for tone’ on the right side.

The task duration of 20 minutes existed of one-third of tone trials and two-thirds of silent trials (which included hallucination and hallucination free periods). The trials were randomized by triplets (Figure 2). Using the Aselect function in Excel, 90 random numbers were created. The highest number of a triplet was assigned to a tone trial. If two highest numbers of two different triplets followed each other, the next highest number of the random numbers was assigned to a tone trial, since two tone trials cannot follow each other up.

After a short interval of approximately a week, patients were invited for the second part of the study. Participants lay in the MRI scanner and could see a screen trough a mirror above their head. The screen displayed the same as in the behavioural part (Figure 1, left). Onset and offsets of an AVH or tone had to be indicated using a MR-compatible button box. Four buttons of the button box were used, one for onset of a tone, one for the end of a tone, one for onset hallucination and one for the end of a hallucination. Responses had to be made with the right hand. Before the scans started the button box was explained to the patient.

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Figure 2. Explanation of Trials 60 Silence trials 30 Tone trials --- 90 trials total 90 random numbers

Tone trials are underlined

Of the first triplet 1, 2, 3, number 1 is the highest number, therefore a tone trial. For the second triplet 5,6,7, number 6 is the highest number, therefore a tone trial.

The rest numbers are silent trials

1. 0,916647 2. 0,566503 3. 0,135895 4. 0,422146 5. 0,064982 6. 0,486672. 7. 0,221852 8. …... etc

During this pilot study, small adjustments were made to the script. These adjustments included adding of two different tone lengths and a change in the jittering of tone lengths. In addition, the script was entirely changed for the last subject. The old script included tone lengths, which were the same as the mean hallucination time of the behavioural task. The new script included the same tone lengths; however the amount of tones was changed to the same as the amount of hallucinations in the behavioural task. For example, if a patient had 30 hallucinations in the behavioural part, with mean hallucination duration of 8 seconds, than the MRI script presented 30 tones with a mean duration of 8 seconds. Consequently, from now on every subject will have a personalized script for the fMRI part.

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Software

The task was programmed in the software programme Presentation. (Neurobehavioral systems, 2011). Tones were created in Audacity. Sinus waves were generated of 500 Hz, which were amplified by 24 Db. In addition, silence wav files were created for the silence trials.

Physiologic measurements

During scanning heart rate and respiration rate were measured. Heart rate was measured with four chest electro cardiology electrodes. Respiration rate was measured using a respiration belt, which was placed around the subject’s abdomen.

Equipment

Auditory stimuli were presented to both ears, using a magnetic resonance (MR) – compatible headphone (MR confon GmBH, Magdeburg Germany). This dual communication system was equipped with software, which subtracts the gradient noise from the patient headphone channel. In addition, the headphone worked according to the electro-dynamic principle and it was driven by the signal of the magnetic field, which stimulated the headphone. Additionally, the headphone is equipped with a high frequency filter.

Data acquisition

A Philips Achieva 3 Tesla clinical MRI scanner (Philips Medical Systems, Best, The Netherlands) was used to obtain scans. During the MRI session, five different scans were made, which took about 35 minutes in total. First, a localizer and a reference scan were collected. Additionally, two-thousand BOLD fMRI scans were acquired with the following parameter settings: slices (coronal)= 40, repetition time= 22.50 msec, echo time= 32.4 msec, flip angle = 10°, field of view = 224 x 256 x 160, voxel size = 4 mm isotropic. The scan sequence accomplished whole brain within 609 msec by the combination of a three-dimensional principle of echo shifting within a train of observation (PRESTO) and parallel imaging sensitivity encoding (SENSE) in two directions, using a eight-channel SENSE head coil (Neggers et al., 2008). Furthermore, an additional functional scan with a flip angle of 27 degrees was acquired. Last, a high-resolution anatomical scan was conducted with the following parameter settings: repetition time = 9.86 msec, echo time = 4.6 msec, voxels = 0.875 x 0.875 x 1, flip angle 8°.

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Preprocessing

The fMRI data were preprocessed and analyzed using Statistical Parametric Mapping (SPM8) (Welcome Trust Centre for Neuroimaging, London). Preprocessing included realignment of within subject images to correct for head motion. The first image was used as a reference to which the rest of the scans were realigned. Subsequently, the anatomical scan was coregistered to the realigned functional scans. The co-registered anatomical scans were then segmented, using unified segmentation. Furthermore, the functional scans and anatomical scan were spatially normalized to a standard Montreal Neurological Institute template based on a T1-weighted scan with high anatomical contrast. At last, images were smoothed using a 8-mm full width at half maximum (FWHM) Guassian kernel.

Statistical analysis of behavioural responses

A paired sample t-test was conducted to evaluate the number of events of both hallucinations and detection of a tone. Another paired sample t-test was performed to examine the mean durations of both hallucinations and detection of a tone. Moreover, the mean total duration of both hallucinations and detection of a tone was also tested with a paired sample t-test.

The characteristics of the hallucinations in the behavioural task and the fMRI task were compared: a paired sample t-test was performed to evaluate the number of hallucinations in both parts of the study, as well as the mean duration of hallucinations in both behavioural and fMRI task, which was also tested with a paired sample t-test. Last, the mean total duration of hallucinations in both tasks was examined using a paired sample t-test.

Statistical analysis of fMRI responses

First level analysis

A model was created using three different conditions. First, the onset of hallucination was used which was indicated by a button press. Another button press indicated the end of a hallucination. The time between the first en the second button press was taken as the duration of a hallucination. Second, the onset of detection of a tone was indicated by another button press. The time between the first button and the second button, which indicated the end of detection, was taken as the duration of detection of a tone. Third, time periods where buttons were pressed both for hallucination and detection of a tone were taken as a covariate. This

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disclose the typical delay in fMRI responses. Furthermore, the model was fitted to the data using general linear model (GLM) estimation (Worsley and Friston, 1995).

In total, four contrasts were defined: Hallucination periods versus baseline, tone periods versus baseline, hallucinations periods versus tone periods and tone versus hallucination periods.

First level analysis was acquired to all contrasts on whole brain level. A one-sample t-test was performed on first level with a threshold of p<0.05.

Conjunction analysis

In addition, a conjunction analysis of the AVH- baseline and Tone- Baseline condition was performed, which allowed to identify common processing differences (Price et al., 1997). A one-sample t-test was performed with a FWE threshold of p<0.05.

Group level analysis

Statistical non-parametric mapping (SnPM) was used to conduct group analysis. The contrasts defined in the first level analysis were used. A one-sample multi subjects t-test was performed with a FWE threshold of p<0.05.

In addition to FWE corrected p<0.05 thresholds, an extended threshold of five voxels is used. In addition, the anatomical label of nearest gray matter of voxels in the table was determined by using Statistical Parametric Mapping (SPM5), with labels of Wake Forest University (WFU) Pickatlas (http://www.fmri.wfubmc.edu/download.htm). The anatomical label of “area” in the table was determined using WFU Pickatlas's Talairach Daemon Labels.

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Results

Clinical evaluation

The mean total PANSS score was 62 (SD 18). The mean score on the positive subscale was 15 (SD 4) and the mean score on the negative scale was 15 (SD 6). The average score on the scale assessing general psychopathology was 32 (SD 10).

Performance during behavioural task

The mean number of hallucinations during the behavioural task was 36 (SD 27; range 19-91). Furthermore, the mean duration of hallucinations was 10 seconds (SD 12; range 2-34) and the mean total hallucination duration was 308 seconds (SD 246; range 56-576). Details about the characteristics of the hallucinations per subject in the behavioural task are summarized in Table 2.

Performance during functional scans

During the functional scan the mean number of hallucinations was 28 (SD 11; range 10-38). The mean duration of hallucinations was 9 seconds (SD 5; range 2-16) and the mean total AVH duration was 249 seconds (SD 186; range 59- 589). Additionally, the mean number of detection of a tone was 16 (SD 8; range 6-29). The mean duration of detection was 10 seconds (SD 13; range 3-36) and the mean total duration of detection was 117 seconds (SD 83; range 31-235). Furthermore, the number of overlap, in which both hallucinations and detection of a tone were indicated, was 2 (SD 3; range 0-8). The mean overlap duration was 3 seconds (SD 3; range 8) and the mean total overlap duration was 8 seconds (11; range 0-25). Details about the characteristics of AVH and detection of tones during the functional scans are summarized per subject in Table 3.

There was a significant difference in the number of hallucinations and the number of detection of a tone, t (5) = 3.373, p= 0.020. The mean durations of both hallucinations and detection of a tone were not significantly different, t (5) = -.094, p= 0.928. Moreover, the mean total duration of both hallucinations and detection of a tone revealed no significant difference, t (5) = 1.539, p= 0.184.

The characteristics of the hallucinations in the behavioural task and the fMRI task did not differ significantly: the number of hallucinations in both parts of the study were not significant different t (5) = 0.949, p=0.386. Furthermore, the mean duration of hallucinations

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in both behavioural and fMRI task, revealed no significant difference t (5) = 1.743, p= 0.142. Last, the mean total duration of hallucinations in both tasks revealed a trend towards significance, t (5) = -2.255, p= 0.074.

Table 2. Characteristics of auditory verbal hallucinations (AVH) in patients with a psychotic

disorder during the behavioural experiment.

Subject N AVH / 20 min Average AVH

length (s) Total AVH duration(s) A. 26 8.8 273.6 B. 22 6.9 575.8 C. 91 1.5 140.9 D. 22 2.6 56.1 E. 41 3.6 153.2 F. 19 34.1 647.9 Mean 37 9.6 307.9

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Table 3. Characteristics of auditory verbal hallucinations and detection of patients with a

psychotic disorder during the fMRI experiment.

fMRI data: first level analysis

Analysis 1: Brain activation during auditory verbal hallucinations: The first analysis

examined brain activation during auditory verbal hallucinations. Brain activation revealed in this analysis for each individual subject is shown in Figure 3A to 3F respectively. Glass brains of each individual subject during AVH are shown in the Supplemental Data respectively in Figure 1A to 1F. Additionally, the details about peak activations during AVH are shown in the Supplemental data Table 1.

For the first subject most extended activation was found in language-related areas including the right inferior frontal gyrus and left supramarginal gyrus. Additionally, activation was found in right and left inferior parietal lobule, right and left middle frontal gyrus and left middle temporal gyrus.

Furthermore, activation during AVH for the second subject was also observed in language-related areas, such as the bilateral superior temporal gyrus and bilateral inferior frontal gyrus. Additionally, motor areas as the bilateral precentral gyrus were also recruited. Furthermore, the right middle frontal gyrus, left superior frontal gyrus, bilateral fusiform

Subject N AVH Averag e AVH length (s) Total AVH duration (s) N detection Average detection length (s) Total detection duration (s) N overlap Average overlap length (s) Total overlap duration (s) A. 28 8.6 240.9 29 8.4 234.7 3 8.4 25.1 B. 37 15.8 589.3 18 5.6 101.3 8 2.9 18.4 C. 38 1.5 58.5 21 2.9 60.9 1 0.8 0.8 D. 21 9.6 201 10 3.1 31 0 0 0 E. 33 9 284 16 3.7 59 1 4.3 4.3 F. 10 12 120 6 35.6 213.4 0 0 0 Mean 28 9.4 249 17 9.9 116.7 2 2.7 8.1

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gyrus, right precuneus, right cuneus were activated, as well as the right postcentral gyrus, left posterior cingulated, right middle temporal gyrus and right lingual gyrus were recruited.

No significant signal changes during hallucinations were observed for the third subject. Moreover, for the fourth subject the most prominent signal change during hallucinations was observed in the bilateral precentral gyrus, cuneus and right inferior parietal lobule. Other significantly activated areas included the left transverse temporal gyrus, cingulate gyrus and superior temporal gyrus.

Furthermore, most prominent activation in the fifth subject during AVH was observed in the right superior frontal gyrus, right and left middle frontal gyrus, right cingulate gyrus, right inferior parietal lobule and right precunues. For the sixth subject, significant activation was observed in the left parahippocampal gyrus

In sum, most prominent signal changes for all subjects were observed in the right inferior frontal gyrus, right middle frontal gyrus, right inferior parietal lobule, left superior temporal gyrus, bilateral precentral gyrus, the right precuneus, right cuneus and cingulate gyrus. An overview of all activated areas during AVH is shown in table 3.

Analysis 2: Brain activation during detection of a tone: Brain activation during detection

of a tone for each individual subject is shown in Figure 3A to 3F respectively. Glass brains of each individual subject during detection of a tone are shown in the Supplemental Data in Figure 1A to 1F. Additionally, the details about peak activations during detection of a tone are shown in the Supplemental data Table 2.

First level analysis of detection of tones revealed activation for the first subject in the right and left superior temporal gyrus, transverse temporal gyrus, middle frontal gyrus, inferior frontal gyrus, precentral gyrus and inferior parietal lobule. Additionally, activation was also found in the right precunues.

For the second subject significant activity was found in right hemispheric areas such as the superior, middle, medial and inferior frontal gyrus, as well as the lingual, precentral, postcentral and cingulate gyrus. Additionally, the right precuneus, insula, cerebellum, as well as the inferior and superior parietal lobule were recruited. Furthermore, significant activation was also found in the left fusiform gyrus, inferior parietal lobule, precuneus and postcentral gyrus.

Moreover, no significant activation was found for the third participant. For the fourth subject significant activation during detection of a tone was observed in the left precentral gyrus.

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For the fifth subject most prominent activation was found in left areas as the middle temporal gyrus, superior temporal gyrus, superior frontal gyrus and the inferior frontal gyrus. Finally, significantly activated areas during detection of tones for the sixth subject were the right inferior frontal and middle temporal gyrus. Additionally, the left precentral gyrus was activated.

In sum, most prominent signal changes during detection of a tone were the right and left inferior frontal gyrus, right middle frontal gyrus, bilateral inferior parietal lobule, bilateral precentral gyrus, left superior temporal gyrus and right precuneus. An overview of all activated areas during detection of a tone is summarized in table 3.

Analysis 3: Conjunction analysis Hallucinations and Detection: The results of the

conjunction analysis for each individual subject is Figure 3A to 3F. Glass brains of each individual subject of the conjunction analysis are shown in the Supplemental Data in Figure 1A to 1F. Additionally, the details about peak activations of the conjunction analysis are shown in the Supplemental data Table 3.

Conjunction analysis of the hallucination versus baseline condition and detection versus baseline condition revealed extensive activations in different brain areas for three subjects, as seen in Figure 3A, 3B and 3D. For the first subject, significant activation was mainly found in the left middle temporal gyrus, right inferior frontal gyrus, as well as the bilateral inferior parietal lobule.

Furthermore, the right precuneus, right middle frontal gyrus, right posterior cingulate and the left fusiform gyrus were found to be significantly activated areas in the second subject. Moreover, the fourth subject only showed significant activation in left precentral gyrus in the conjunction analysis. Finally, the conjunction analyses in the third, fifth and sixth subject revealed no significant activation.

The results of the analysis of auditory verbal hallucinations versus detection of a tone and the analysis of detection of a tone versus auditory verbal hallucinations are presented in the supplemental data. Additionally, the results of the second level analysis are also shown in the supplemental data.

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Table. 3 Overview activated brain areas during auditory verbal hallucinations and detection of a tone

AVH Stimulus detection

Subject Area MNI

Coordinate s

p t Cluster size Area MNI

Coordinates

p t Cluster

size

x,y,z x, y, z

A. Right inferior frontal gyrus Left middle frontal gyrus Right middle frontal gyrus Left inferior parietal lobule Right inferior parietal lobule Left middle temporal gyrus Left supramarginal gyrus

46, 20 -2 -38, 44, 10 30, 56, 14 -42, -64, 46 42, -52, 46 -54, -36, 2 -46, -52, 30 0.000 0.000 0.003 0.000 0.000 0.000 0.002 6.61 5.50 5.02 6.06 5.61 6.23 5.11 43 11 12 33 46 33 11

Right inferior frontal gyrus Left middle frontal gyrus Right middle frontal gyrus Left inferior parietal lobule Right inferior parietal lobule Left superior temporal gyrus Right superior temporal gyrus Left transverse temporal gyrus Right transverse temporal gyrus

Left inferior frontal gyrus Left precentral gyrus Right precentral gyrus Right precuneus 42, -56, 54 -34, 40, 14 42, 12, 50 -42, -52, 46 42, -56, 54 -50, -12, 2 58, 12, 2 -50, -12, 2 58, 12, 2 -42, 16, 26 -38, -20, 58 42, 12, 18 6, -64, 46 0.000 0.019 0.001 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.005 0.000 0.010 7.21 4.61 5.70 5.49 5.81 15.37 12.53 15.37 12.53 5.57 4.93 5.69 4.75 58 5 26 40 60 330 296 330 296 12 7 34 6

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B. Left inferior frontal gyrus Right inferior frontal gyrus Right middle frontal gyrus Left superior frontal gyrus Left fusiform gyrus Right lingual gyrus Right precuneus Right postcentral gyrus Right precentral gyrus Left superior temporal gyrus Right superior temporal gyrus

Left posterior cingulate Right middle temporal gyrus Right fusiform gyrus

Right cuneus

Left precentral gyrus

-42, 32, -14 42, 28, -14 6, -20, 74 -10, 0, 74 26, 76, -22 10, -80, -14 18, -76, -26 54, -20, 54 54, -20, 54 -62, -24, 10 66, -8, 2 -2, 40, 6 42, -76, -26 50, -64, -22 18, -96, 2 -58, -8, 38 0.000 0.000 0.000 0.000 0.007 0.000 0.000 0.000 0.000 0.001 0.000 0.000 0.000 0.003 0.000 0.002 5.53 5.73 7.46 6.08 5.92 5.52 5.61 5.49 5.49 5.25 5.78 6.37 5.61 5.02 4.80 5.07 7 16 24 9 45 10 14 33 33 14 28 35 14 7 5 17

Right superior parietal lobule Right inferior frontal gyrus Right middle frontal gyrus Right superior frontal gyrus Left fusiform gyrus

Right lingual gyrus Right precuneus Right postcentral gyrus Right precentral gyrus Right medial frontal gyrus Left inferior parietal lobule Right inferior parietal lobule Right cingulate gyrus

Left precuneus

Right frontal sub-gyral Right declive

Right anterior cingulate Left postcentral gyrus

26, -76, 46 66, 4, 18 34, 32, 46 6, 48, -6 22, 84, -18 10, -84, -14 2, -60, 30 18, -52, 66 66, 4, 18 6, 48, -6 -46, -72, 38 50, -48, 54 2, -60, 30 -18, -80, 46 30, -16, 30 26, -64, -22 6, 12, -10 -38, -32, 62 0.000 0.000 0.000 0.000 0.001 0.002 0.000 0.000 0.000 0.001 0.003 0.000 0.000 0.000 0.002 0.000 0.010 0.000 8.41 5.84 5.62 5.91 5.19 5.16 7.08 6.72 5.84 5.91 5.02 5.59 7.08 6.31 5.12 5.94 4.75 5.65 106 9 11 11 35 7 101 78 9 11 5 14 101 9 24 8 11 13

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C. - - - - D. Left precentral gyrus

Right inferior parietal lobule Right precentral gyrus Left superior temporal gyrus Left transverse temporal gyrus

Left cingulate gyrus Left cuneus Right cuneus -46, -16, 50 58, -28, 26 58, -28, 26 -50, 0, 2 -50, -24, 10 -2, -4, 50 -6, -100, 2 -6, -100, 2 0.000 0.000 0.000 0.001 0.000 0.000 0.000 0.000 6.67 6.18 6.18 5.30 5.99 5.47 6.36 6.36 93 81 81 10 39 33 73 73

Left precentral gyrus -42, -16, 54 0.001 5.42 21

E. Right superior frontal gyrus Right middle frontal gyrus Left middle frontal gyrus Right inferior parietal lobule Right cingulate gyrus

Right precuneus 30, 20, 58 30, 20, 58 -34, 48, 22 38, -68, 46 10, -40, 34 2, -60, 42 0.000 0.000 0.005 0.010 0.001 0.013 6.31 6.31 4.94 4.79 5.27 4.72 23 23 6 6 12 7

Left superior frontal gyrus Left middle temporal gyrus Left superior temporal gyrus Left inferior frontal gyrus Left inferior frontal gyrus

-6, 8, 58 -66, -32, -6 -66, -32, -6 -46, 32, -6 -54, 16, 14 0.000 0.000 0.000 0.000 0.000 7.70 6.87 7.70 6.29 5.18 36 12 36 11 14

F. Left parahippocampal gyrus 30, 16, -34

0.000 5.45 6 Right inferior frontal gyrus Right middle temporal gyrus Left precentral gyrus

54, 12, -2 38, -16, -10 -22, -20, 70 0.000 0.000 0.000 7.80 7.64 5.18 50 41 19

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Figure 3A. Areas of significant activation in first level analysis in subject A.

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Figure 3C. Areas of significant activation in first level analysis in subject C.

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Figure 3E. Areas of significant activation in first level analysis in subject E.

Figure 3F. Areas of significant activation in first level analysis in subject F.

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Discussion

This is the first study to examine and compare brain activation during hallucinations and simple auditory stimulus detection in 6 patients with a schizophrenia-spectrum disorder. The conjunction analysis, which identifies voxels that are activated in both hallucinations and stimulus detection, revealed no areas that were significant activated in more than one subject. However, if we look at the conjunction analysis per individual, areas as the left middle temporal gyrus, right inferior frontal gyrus, bilateral inferior parietal lobule showed overlapping activation, as well as the right precuneus, right middle frontal gyrus, right posterior cingulate gyrus, left fusiform gyrus and the left precentral gyrus were.

Furthermore, during hallucinations most prominent signal changes were found in the right inferior frontal gyrus, right middle frontal gyrus, right inferior parietal lobule, left superior temporal gyrus, bilateral precentral gyrus, right precunues, right cuneus and left cingulate gyrus. During detection of a tone, the right and left inferior frontal gyrus, right middle frontal gyrus, bilateral inferior parietal lobule, bilateral precentral gyrus, left superior temporal gyrus and right precuneus were significantly activated.

Conjunction analysis

These results suggest that during detection and hallucinations comparable areas are activated. The same areas were also observed by Bledowski and co-workers (Bledowski et al., 2005), who performed a visually oddball task with healthy subject. They found also activation in the left precentral gyrus, bilateral inferior parietal lobule, right inferior and middle frontal gyrus and right cingulate gyrus. They also observed recruitment of the right precentral, bilateral insula, left postcentral gyrus and right superior temporal gyrus. Additionally, Copolov and colleagues (Copolov et al., 2003) who examined activation during hallucinations, showed also activation in the right middle an inferior frontal gyrus, and additional areas as the left superior temporal gyrus, parahippocampal gyrus, posterior cingulate gyrus and the right middle temporal gyrus.

Auditory verbal hallucinations

These areas found during hallucinations were similar to those observed by Diederen and colleagues, (Diederen et al, 2010), who studied brain activation preceding and during hallucinations. In that study, the right inferior and middle frontal gyrus, right inferior parietal

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lobule, left superior temporal gyrus, bilateral precentral gyrus were also implicated. However, Diederen and colleagues discovered also additional activated areas, including the left inferior parietal lobule, left inferior frontal gyrus, as well as the right middle and superior temporal gyrus. Additionally, activation was found in bilateral supramarginal gyrus, insula, postcentral gyrus, superior frontal gyrus and cerebellum. Since Diederen and co-workers performed their study on a larger subject group, this could explain the additional areas.

Stimulus Detection

The present results about stimulus detection are in line with previous stimulus detection studies, in which similar areas were observed. For example, Hampshire and colleagues (Hampshire et al, 2009) performed a target detection task, in which targets revealed activation in the right inferior frontal gyrus, right middle frontal gyrus, right inferior parietal lobule and left inferior frontal gyrus. These areas were also observed during detection of a tone in our study. Additionally, they also observed activation in the right superior frontal, cingulate, middle and superior temporal gyrus, as well as the right insula.

Furthermore, Kiehl and co-workers, (Kiehl et al, 2005), who examined stimulus detection in schizophrenia patients, also described the same network during detection,

However, we expected to find more temporal activation for detection of the tones, as previous studies showed that detection of auditory target stimuli activates the auditory cortex (Stevens et al, 2000). In this study an auditory oddball task was performed, in which the target tone differed in frequency from the standard tone. Target detection recruited similar detection areas as our study showed, namely the auditory cortex, as well as the left inferior parietal lobule, right middle frontal gyrus, right inferior frontal gyrus, bilateral superior temporal gyrus. The lack of temporal activation in our study could be due to the short total tone duration that was presented, which was shorter than two minutes in total for four of the six subjects. Additionally, it could be that the tone was not distinctive enough due to the scanner noise or due to habituation.

As the results of the conjunction analysis show, comparable areas are activated during hallucinations and detection, as the left middle temporal gyrus, right inferior frontal gyrus, bilateral inferior parietal lobule showed activation, as well as the right precuneus, right middle frontal gyrus, right posterior cingulate gyrus, left fusiform gyrus and the left precentral gyrus.

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Some of these areas, were also found in both separate analysis of AVH and detection, as the right inferior and middle frontal gyrus, right inferior parietal lobule, left precentral gyrus and right precuneus. However, the exact peak location within the activated areas differed between both separate analyses. Nevertheless, comparable areas are observed if we consider both the conjunction analysis and if we look at the separate analysis.

Apart from potential overlap in activation of both conditions, of particular interest was to discover brain areas, which were activated specifically for hallucinations. Our results from the hallucination analysis showed activated areas that were also found in the conjunction analysis. However, if we look at activated areas that were found during the AVH analysis but were not found in the conjunction analysis, perhaps this could explain an AVH specific area. In this study the left superior temporal gyrus, right precuneus, right precentral gyrus and the left cingulate gyrus were found in the AVH analysis and not in the conjunction. This could suggest that these areas are specific for AVH.

Consequently, it could be argued that more cognitive processes are measured than purely AVH when one is measuring hallucinations. For example, a part of the found hallucination brain activity could be explained as detection of hallucinations; namely, in this pilot study the activated networks for both AVH and detection seems to be somewhat comparable. Additionally, other cognitive processes could also explain parts of the activation found during AVH, for example button presses, or thinking about something else. However, in this study we are particularly interested in the activation that is specific for AVH and the comparison with detection. Therefore, this study could give more insight in the precise location of AVH activity, by excluding the activation due to detection. Nevertheless, as the left superior temporal gyrus, cingulate gyrus and the right cuneus and precentral gyrus could be candidates for a better understanding of the origin of hallucinations; still other cognitive aspects could recruit these areas. This study does show that at least for detection there is a great overlap in brain network activation.

Limitations and Suggestions for further research

During this entire study small adjustments were made to the task, since it was a pilot study, to make the task more suitable. However, it could have happened that different datasets are measured with a different set-up. Therefore, subjects might be less comparable. Furthermore,

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less auditory cortex activation was found during detection than expected, this could be due to the short duration of tone presentation. Namely, four subjects had a total detection time smaller than two minutes, which is quite low in contrast to a twenty minutes task. This short total duration of tones was due to the distribution of tone and silence periods in the old script. This script had both silence and tone trials, in which a hallucination could happen in a silence period, but a silence trial could only end if a hallucination occurred. Therefore, the one-third, one-third, one-third distribution between hallucinations, silence and tone trials as was planned to have, did not exceed. However, this is correctly improved for the last subject (subject A). This new script seems to give a more equal distribution between hallucination, tone and silent periods, because this script has a solid amount of tones is presented, which is equal to the amount of hallucinations in the behavioural task. This improved script could eventually lead to more power in the analysis. As this study shows, a total tone length of at least 200 seconds results in a clear activation pattern.

Noise from the scanner could also contribute to less distinctiveness of tones, though all tones were reported correctly. The hearing threshold of subjects could also differ, possibly influencing behavioural results. However, accuracy was 100 % for all subjects, rendering this explanation unlikely. During this study the respiration and heart rate were measured. However, the data was not corrected for both physiological measurements, which could be a limitation of this study.

Finally, two subject had only two minutes or shorter of total hallucinations, which is quite low compared to twenty minutes of task. Nevertheless, this study consisted of a pilot study, therefore all participants were analysed. In the larger study subjects with a low amount of hallucinations would be excluded. Future studies should focus on these points.

In sum, we observed similar and comparable activated brain areas during hallucinations and detection of a tone in the conjunction analysis, as the left middle temporal gyrus, right inferior frontal gyrus, bilateral inferior parietal lobule, as well as the right precuneus, right middle frontal gyrus, right posterior cingulate gyrus, left fusiform gyrus and the left precentral gyrus were observed. Additionally, the right cuneus, right precentral gyrus, left superior temporal gyrus and left cingulate gyrus seemed to be specifically activated during hallucinations. However, this pilot study included only a small number of subjects: an increase in the amount of subjects could reveal a more specific network for AVH.

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to detection of these hallucinations and performing a motor response to indicate them, which could explain the overlap in brain activation with detection of a tone and indicate them through button-press. Therefore, these results highlight the importance of the right cuneus, right precentral gyrus, left superior temporal gyrus and left cingulate gyrus in AVH, which suggest that in the future, treatment for hallucinations could be focused on these areas.

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Acknowledgements

I would like to thank Iris Sommer for giving me the opportunity to perform my internship at her lab. I would like to thank Kirstin Daalman, for introducing me to this project and for the help with patient contact. I would like to thank Kelly Diederen en Remko van Lutterveld for multiple reasons: First, for giving me the opportunity to think along with the decisions about the research design. Additionally, I would like to thank them for always being available and helpful if I had any questions. Especially, I would like to thank them for the great knowledge, the independency and the academic skills I have learned during this project. Furthermore, I would like to thank Bram Zandbelt for the help and tips for the research design. I would like to thank Stanimira Georgiva for the great help on programming the task. I would also like to thank Lucas Coppes for helping out with many little problems and questions. Also, I would like to thank Anne Lotte Meijering for the help with scanning of participants and also openness to questions I had, and with that I would like to thank all my Spectrum colleagues for the great help they always offered. I had a great time at Utrecht and I think I have grown during this project in an academic, a professional and an independent way.

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Supplemental Data

Figure 1A: Glass Brains 1st Level analysis for subject A.

Subject: A

FWE p< 0.05 AVH – Baseline FWE p<0.05 Tone- Baseline

T= 4.37 T=4.37

FWE p< 0.05 Conjunction AVH-Baseline/ Tone- Baseline

T= 4.37

FWE p< 0.05 AVH-Tone FWE p< 0.05 Tone - AVH

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Figure 1B: Glass Brains 1st Level analysis for subject B.

Subject: B

T= 4.36 T= 4.36

T= 4.36

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Figure 1C: Glass Brains 1st Level analysis for subject C.

Subject: C

T= 4.41 T= 4.41

T= 4.41

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Figure 1D: Glass Brains 1st Level analysis for subject D.

Subject: D

T= 4.4 T= 4.4

T= 4.4

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Figure 1E: Glass Brains 1st Level analysis for subject E

Subject: E

T= 4.38 T=4.38

T= 4.38

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Figure 1F: Glass Brains 1st Level analysis for subject F.

Subject: F

T= 4.21 T= 4.21

T= 4.21

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Supplemental data

Analysis 4: Brain activation during Hallucinations versus Detection: Brain activation

during hallucinations versus detection for each individual subject is shown in the supplemental data Figure 2A to 2F. Glass brains of each individual subject during hallucinations versus detection are shown in the supplemental data in Figure 1A to 1F respectively. Additionally, the details about peak activations during hallucinations versus detection are shown in the supplemental data in Table 4.

For subject A, most prominent activation was found in the right fusiform gyrus and the right cuneus. Furthermore, for the second subject highly significant activated areas included right postcentral gyrus, middle frontal gyrus and middle temporal gyrus. Additionally, bilateral superior temporal gyri were also activated, as well as the left inferior frontal gyrus.

For the third subject, most prominent signal change was found in the left superior frontal gyrus. Moreover, the analysis showed left cuneus activation for the fourth subject.

Most prominent signal changes of hallucinations minus detection activation for the fifth subject were right hemispheric areas as the cingulate gyrus, middle frontal gyrus, inferior parietal lobule as well as left hemispheric areas as the transverse temporal gyrus and superior parietal lobule. In addition, bilateral precuneus , the right postcentral gyrus, left lingual gyrus and left medial occipitaltemporal gyrus were also significantly activated.

Finally, significantly activation for the sixth subject was found in bilateral superior temporal gyrus, right middle frontal gyrus, right ligual gyrus, right cuneus, left middle occipital gyrus, right parietal sub-gyral and the left angular.

In sum, most prominent activation in the analysis of hallucination activation versus detection activation was observed in the right middle frontal gyrus and bilateral superior temporal gyri.

Analysis 5: Brain activation during Detection versus Hallucinations: Brain activation

during detection versus hallucinations for each individual subject is shown in the supplemental data in Figure 2A to 2F. Glass brains of each individual subject during detection versus hallucinations are shown in the supplemental data in Figure 1A to 1F. Additionally, the details about peak activations during detection versus hallucinations are shown in the supplemental data in Table 5.

The analysis of detection activation minus hallucination activation revealed highly significant activations in bilateral superior temporal and transverse temporal gyri for the first

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subject. Furthermore significant activation was also observed in the left postcentral and precentral gyri, as well as the right middle frontal gyrus and right insula.

For the second subject mainly right hemispheric areas were activated as the precuneus, superior parietal lobule, postcentral gyrus, precentral gyrus, inferior parietal lobule, frontal sub-gyral and cingulate gyrus. Additionally, the left precentral and postcentral gyrus and precuneus were activated.

Moreover, the third and fourth subject showed no significant activation in the analysis of detection minus hallucinations. Left hemispheric areas were significant activated during detection versus hallucination analysis for the fifth subject, such as the middle temporal gyrus, superior temporal gyrus, superior frontal gyrus and inferior frontal gyrus. Additionally, the right inferior frontal gyrus was also recruited.

Finally, for the last subject most prominent signal changes were observed in the right inferior frontal gyrus, left postcentral and precentral gyri, left insula and the right declive.

In sum, most prominent findings in the analysis of detection versus hallucination activation were the left superior temporal gyrus, left postcentral gyrus and left precentral.

Second Level

Analysis 6: Group analysis brain activation during hallucinations: Group analysis of

brain activation during hallucinations showed no significant effects.

Analysis 7: Group analysis brain activation during Detection: Group analysis of detection

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Figure 2A.

Areas of significant activation in first level analysis in subject A.

Figure 2B

Areas of significant activation in first level analysis in subject B.

Figure 2C.

Areas of significant activation in first level analysis in subject C.

Figure 2D.

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Figure 2E.

Areas of significant activation in first level analysis in subject E.

Figure 2F.

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Table 1. Significantly activated voxels and location of local maxima during auditory verbal

hallucinations in patients with psychotic disorder (1).

Subject Area Montreal Neurological Institute

Coordinates

p t Cluster

size x, y, z

A. Right inferior frontal gyrus 46, 20 -2 0.000 6.61 43

Left middle temporal gyrus -54, -36 , 2 0.000 6.23 33

Left inferior parietal lobule -42, -64, 46 0.000 6.06 33 Right inferior parietal lobule 42, -52, 46 0.000 5.61 46

Left middle frontal gyrus -38, 44, 10 0.000 5.50 11

Left supramarginal gyrus -46, -52, 30 0.002 5.11 11

Right middle frontal gyrus 30, 56, 14 0.003 5.02 12

B. Right middle frontal gyrus 6, -20, 74 0.000 7.46 24

Left posterior cingulate -2, -40, 6 0.000 6.37 35

Left superior frontal gyrus -10, 0, 74 0.000 6.08 9

Left fusiform gyrus -26, -76, -22 0.000 5.92 45

Right superior temporal gyrus/ right postcentral gyrus

66, -8, 2 0.000 5.78 28

Right inferior frontal gyrus 42, 28, -14 0.000 5.73 16

Right middle temporal gyrus 42, -76, -26 0.000 5.63 8

Right precuneus 18, -76, 50 0.000 5.61 14

Left inferior frontal gyrus -42, 32, -14 0.000 5.53 7

Right lingual gyrus 10, -80, -14 0.000 5.52 10

Right postcentral gyrus/ right precentral gyrus

54, -20, 54 0.000 5.49 33

Right precuneus 6, -60, 30 0.000 5.44 10

Left superior temporal gyrus -62, -24, 10 0.001 5.25 14

Right fusiform gyrus 50, -64, -22 0.003 5.02 7

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Subject Area Montreal Neurological Institute Coordinates t Cluster size x, y, z C. - - - -

D. Left precentral gyrus -46, -16, 50 0.000 6.67 93

Left cuneus/ right cuneuss -6, -100, 2 0.000 6.36 73

Right inferior parietal lobule/ right precentral gyrus

58, -28, 26 0.000 6.18 81

Left transverse temporal gyrus -50, -24, 10 0.000 5.99 39

Left cingulate gyrus -2, -4, 50 0.000 5.47 33

Left superior temporal gyrus -50, 0, 2 0.001 5.30 10

E. Right superior frontal gyrus/ right middle frontal gyrus

30, 20, 58 0.000 6.31 23

Right cingulate gyrus 10, -40, 34 0.001 5.27 12

Right inferior parietal lobule 38, -68, 46 0.010 4.79 6

Right precuneus 2, -60, 42 0.013 4.72 7

F. Left parahippocampal gyrus -30, -16, -34 0.000 5.45 6

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Table 2. Significantly activated voxels and location of local maxima during detection of a

tone in patients with psychotic disorder (2).

Subject Area Montreal Neurological Institute

Coordinate

p t Cluster

size x, y, z

A. Left superior temporal gyrus/ left transverse temporal gyrus

-50, -12, 2 0.000 15.37 330

Right superior temporal gyrus/ right transverse temporal gyrus

58, 12 , 2 0.000 12.53 296

Right inferior parietal lobule 42, -56, 54 0.000 5.81 60

Right precentral gyrus 42, 12, 18 0.000 5.69 34

Left inferior frontal gyrus -42, 16, 26 0.000 5.57 12

Left inferior parietal lobule -42, -52, 46 0.000 5.49 40

Right precuneus 6, -64, 46 0.010 4.75 6

B. Right superior parietal lobule/ right precuneus

26, -76, 46 0.000 8.41 106

Right precuneus/ right cingulated gyrus

2, -60, 30 0.000 7.08 101

Right postcentral gyrus/ right medial frontal gyrus

18, -52, 66 0.000 6.72 78

Left precuneus -18, -80, 46 0.000 6.31 18

Right declive 26, -64, -22 0.000 5.94 8

Right medial frontal gyrus/ right superior frontal gyrus

6, 48, -6 0.000 5.91 11

Right precentral gyrus/ right inferior frontal gyrus

66, 4, 18 0.000 5.84 9

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Subject Area Montreal Neurological Institute Coordinates

t Cluster

size x, y, z

Left postcentral gyrus -38, -32, 62 0.000 5.65 13

Right middle frontal gyrus/ right superior frontal gyrus

34, 32, 46 0.000 5.62 11

Right inferior parietal lobule 50, -48, 54 0.000 5.59 14 Right medial frontal gyrus/

right superior frontal gyrus

6, 48, 46 0.001 5.31 9

Right frontal sub-gyral 30, -16, 30 0.002 5.12 24

Left inferior parietal lobule -46, -72, 38 0.003 5.02 5

Right anterior cingulate 6, 12, -10 0.010 4.75 11

C. -

E. Left middle temporal gyrus/ left superior temporal gyrus

-66, -32, -6 0.000 7.70 36

Left superior frontal gyrus -6, 8, 58 0.000 6.87 13

Left inferior frontal gyrus -46, 32, -6 0.000 6.29 11

F. Right inferior frontal gyrus 54, 12, -2 0.000 7.80 50

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Table 3. Significantly activated voxels and location of local maxima of conjunction analysis

AVH- baseline and Tone- baseline of patients with psychotic disorder (3).

Subject Area Montreal Neurological Institute

Coordinates

p t Cluster

size x, y, z

A. Left middle temporal gyrus -54, -40, 2 0.000 6.00 11

Right inferior parietal lobule 42, -52, 50 0.000 5.43 28 Left inferior parietal lobule -42, -56, 46 0.001 5.28 9

B. Right middle frontal gyrus 2, -24, 74 0.000 5.74 8

Right precuneus 18, -76, 50 0.000 5.61 11

Right precuneus 6, -60, 30 0.000 5.44 8

Right posterior cingulate 2, -44, 6 0.017 4.62 5

C. -

E. -

F. -

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Table 4. Significantly activated voxels and location of local maxima of AVH – Tone contrast

of patients with psychotic disorder (4).

Subject Area Montreal Neurological Institute

Coordinates

p t Cluster

size x, y, z

A. Right cuneus 14, -88, 30 0.000 5.49 7

Right fusiform gyrus 26, -84, -22 0.002 5.15 15

B. Right postcentral gyrus/ right superior temporal gyrus

46, -24, 34 0.000 7.66 140

Right middle frontal gyrus 42, 48, -10 0.000 7.22 30

Left superior temporal gyrus -58, -48, 14 0.001 5.35 12

C. Left superior frontal gyrus -10, 68, 22 0.004 5.04 12

D. Left cuneus -2, -88, 30 0.001 5.32 13

E. Right cingulate gyrus/ right precuneus

10, -36, 42 0.000 6.62 244

Right inferior parietal lobule 38, -68, 46 0.001 5.38 13 Left transverse temporal gyrus -46, -24, 10 0.002 5.20 12 Left superior parietal lobule/

left precunues

-30, -60, 46 0.002 5.15 32

Right postcentral gyrus 66, -24, 18 0.004 4.99 5

Left medial occipitotemporal gyrus

-2, -72, -10 0.005 4.94 6

Left lingual gyrus -18, -72, -14 0.006 4.91 7

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Subject Area Montreal Neurological Institute Coordinates

t Cluster

size x, y, z

F. Right superior temporal gyrus 58, -60, 14 0.000 7.03 27

Left superior temporal gyrus -46, 24, -22 0.000 6.66 10

Right lingual gyrus/ right cuneus

14, -80, -14 0.000 6.21 40

Left middle occipital gyrus -34, -88, -2 0.000 5.60 38

Left supramarginal gyrus -50, -56, 30 0.000 5.35 11

Right middle frontal gyus 34, 16, 26 0.000 5.35 18

Right parietal sub-gyral 18, -52, 22 0.001 5.10 21

Left angular gyrus -34, -72, 30 0.006 4.75 13

Comparing brain activation during auditory verbal hallucinations to stimulus detection – a pilot study