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BRAIN
A JOURNAL OF NEUROLOGY
1 Brain Research Unit, Low Temperature Laboratory and Advanced Magnetic Imaging Centre, Helsinki University of Technology, Espoo, Finland
2 Department of Psychiatry, University of Helsinki, Helsinki, Finland
3 Department of Psychiatry, University of Kuopio and University Hospital of Kuopio, Kuopio, Finland
4 Kellokoski Hospital, Kellokoski, Finland
5 Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland
6 Department of Clinical Neurophysiology, Helsinki University Central Hospital, Helsinki, Finland
Distortion of the sense of reality, actualized in delusions and hallucinations, is the key feature of psychosis but the underlying
neuronal correlates remain largely unknown. We studied 11 highly functioning subjects with schizophrenia or schizoaffective
disorder while they rated the reality of auditory verbal hallucinations (AVH) during functional magnetic resonance imaging
(fMRI). The subjective reality of AVH correlated strongly and specifically with the hallucination-related activation strength of the
inferior frontal gyri (IFG), including the Broca’s language region. Furthermore, how real the hallucination that subjects experi-
enced was depended on the hallucination-related coupling between the IFG, the ventral striatum, the auditory cortex, the right
posterior temporal lobe, and the cingulate cortex. Our findings suggest that the subjective reality of AVH is related to motor
mechanisms of speech comprehension, with contributions from sensory and salience-detection-related brain regions as well as
circuitries related to self-monitoring and the experience of agency.
Keywords: brain; functional magnetic resonance imaging; reality distortion; auditory verbal hallucination; inferior frontal gyrus
Abbreviations: AVH = auditory verbal hallucination; IFG = inferior frontal gyrus; HRF = haemodynamic response function;
PANSS = Positive and Negative Syndromes Scale; SRH = subjective reality of hallucinations; VAS = visual analogue scale
Received April 2, 2009. Revised May 28, 2009. Accepted June 7, 2009. Advance Access publication July 20, 2009
ß The Author(s) 2009. Published by Oxford University Press on behalf of Brain.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/
2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Reality of hallucinations Brain 2009: 132; 2994–3001 | 2995
non-hallucination periods. For this analysis, we used the SPM2 psy- lobe implicated in agency (Tankersley et al., 2007), the anterior and
chophysiological interaction tool (Friston et al., 1997) that compares posterior cingulate cortices related to self-monitoring (Northoff and
the context-specific (here, AVH-specific) contribution of brain regions Bermpohl, 2004) and agency (Tomlin et al., 2006), and the striatum
to each other, referred to as ‘coupling’. Following the procedures of involved in the subjective saliency of percepts and in antipsychotic
previous studies (Macaluso et al., 2000; Stephan et al., 2003; Pasley medication (Kapur, 2003; Agid et al., 2007).
et al., 2004; Bingel et al., 2007), we extracted fMRI signals from the To define correlation coefficients, we split data into two indepen-
seed regions (one for the left and another for the right IFG) for each dent sets (Kriegeskorte et al., 2009): we gave a serial number to each
session in which AVH were signalled. The seed regions were spheres of the 10 subjects who participated in two or more fMRI sessions, and
with an 8-mm radius, including 33 voxels, and with their centres at – to each subject’s fMRI session. For the first data set, we created
52, 20, 8 in the left IFG, and at 52, 12, 12 in the right IFG (x, y, z contrast images of sessions with an odd number for the subjects
coordinates in the Talairach system); the coordinates were found by with odd number and of sessions with even number for the subjects
visually estimating the centre of gravity in the area of maximum with even number. For the second data set the odds and evens were
group-level correlation of AVH-related activation with the SRH. reversed. We calculated the individual mean SRH values for both data
Because coupling between brain regions occurs at the level of sets as described above and conducted two independent correlation
neuronal signalling rather than at the level of haemodynamics analyses both with activation and coupling. We defined voxels of
(Gitelman et al., 2003), we deconvolved the fMRI time courses to maximum correlation (P50.05, uncorrected) in the regions of interest
estimate the neuronal signal without the haemodynamic lag. We from one data set and extracted r-values from these voxels from
then created a regressor for hallucination versus non-hallucination the other data set.
periods, and multiplied it by the deconvolved time course from Any difference between correlations of the SRH with the IFG and
the IFG. We ran a new general linear model (GLM) analysis using the temporal lobe activation was tested using a z test (Tabachnick and
this regressor, mean-normalized and reconvolved with the HRF. We Fidell, 2001). Because we compared correlations rather than slopes of
added the box-car regressor for hallucination versus non-hallucination regression lines, the results indicate whether inter-individual variation
periods, convolved with the HRF, to the model to remove the of AVH-related brain activation explains the SRH significantly better in
AVH-related activation. Therefore, the results reflect coupling during one than in another brain region. The functional images were overlaid
the activation rather than the AVH-related activation. Button-press on an SPM template and a MATLAB program was used to convert
regressors and movement regressors were applied as in the activation MNI (Montreal Neurologic Institute) coordinates to the Talairach
analysis, and the original fMRI-time course from the IFG was added to system (MNTI2TAL, author M. Brett, http://www.mrc-cbu.cam
remove the coupling beyond the contrast of interest. Therefore, the .ac.uk/Imaging/Common/mnispace.shtml).
model specifically tested for the contrast of coupling of the IFG with
other brain regions during AVH versus non-AVH periods. One-sample
t test was used to test resulting contrast images, at the group level,
for hallucination-related changes in the connectivity of the IFG with
Results
other parts of the brain. Finally, we correlated these contrast images
voxel-wise with the SRH across subjects. Subject characteristics
We reanalysed the data to exclude contribution of possible global
Seven subjects had schizophrenia and the remaining four had a
confounds that could arise from respiration or other movements. In
closely related schizoaffective disorder, as defined in the
the re-analysis, carried out at the individual level in the same way as
Diagnostic and Statistical Manual of Mental Disorders IV (1994).
was the first psychophysiological interaction analysis, we normalized
the global mean values by scaling the average voxel value to zero. The subjects matched the normal population in cognitive perfor-
These normalized contrast images of AVH-specific coupling were then mance (Supplementary Table 1), lived in the community and four
used for second correlation analysis with the SRH. subjects worked full time. Except for hallucination evaluations,
the subjects’ PANSS (Kay et al., 1987) scores were low (mean
total score 56, range 40–85; Supplementary Table 1). The two
Statistical methods VASs of the SRH, presented with different wordings, correlated
Statistically significant activation refers to anatomically meaningful with each other (r = 0.89, P50.001) and written descriptions of
activation in the a priori regions with P50.005 for each of 420 the hallucinations were coherent. All subjects reported hearing
contiguous voxels (corresponding to P50.0007, uncorrected), or for words or sentences that no one else heard. They attributed
the correlation with coupling, P50.005, uncorrected, at the cluster
these experiences to an unknown origin or to their psychiatric
level (based on single voxel values and the extent of activated
disease. None of the subjects reported supernatural beliefs about
voxels according to random field theory). We selected this latter liberal
threshold to avoid false negative findings in testing the hypothesis
voices, although many of them had held such beliefs before.
about involvement of the large-scale neuronal network. Note, how- Six subjects believed that the AVH had a meaning of their own:
ever that most findings are of much higher statistical significance. For to comment, to contact, to accuse, to punish, or to tell them what
the AVH-related brain activations, the a priori regions included those to do.
repeatedly activated during the AVH in previous studies (Allen et al.,
2008): the IFG, the anterior cingulate cortex, the parahippocampal
gyrus, and the superior and middle temporal gyri. For the correlation
Correlations between subjective reality
between the SRH and coupling, additional a priori regions included and other subjective dimensions of
those brain areas associated with the factors believed to contribute hallucinations
to reality distortion: the posterior parietal cortices related to self-
monitoring and the experience of agency (Jeannerod and Pacherie, The mean SRH was similar in subjects who did and did not believe
2004; Frith, 2005; Allen et al., 2007), the right posterior temporal AVHs to have a meaning of their own (43 and 48 of 100,
2998 | Brain 2009: 132; 2994–3001 T. T. Raij et al.
Figure 2 Correlation between AVH-related brain activation and the SRH. Brodman areas 44 and 45 (the Broca’s region and its right
homologue) are marked according to cytoarchitectonical maps by Eickhoff et al. (2005). Right: the colour scale for statistical
significance.
Figure 3 Positive correlations between hallucination-related coupling (in parameter estimates) and the SRH. The coupling refers to the
difference with the left IFG (x, y, z = –52, 20, 8) during hallucinations versus non-hallucination periods. The stronger the SRH, the
stronger the coupling of the IFG with the right ventral striatum (A), the middle right anterior cingulate cortex (B), the right posterior
temporal lobe (C), the auditory cortex (D), and the left nucleus accumbens (E). (F) The colour scale for statistical significance.
(range 10–162, mean duration 23 s, range 1–365 s) occurred per pregenual cingulate cortex (P = 0.002). These negative correlations
subject during the fMRI recordings. Individual average SRH ranged remained significant with the application of global normalization in
from 9 to 86 (Supplementary Table 1), and AVH-related brain the reanalysis (P50.001).
activation resembled activations observed in previous studies,
including the right parahippocampal cortex, the bilateral IFG, the
right posterior temporal lobe, the left anterior temporal lobe, and
the right anterior cingulate cortex (Supplementary Fig. 1 and
Discussion
Supplementary Table 3). These combined fMRI and SRH results provide new insights into
The strength of AVH-related activation in the IFG, correspond- the brain mechanisms of reality distortion during AVH related to
ing to the Broca’s region and its right-hemisphere homologue, schizophrenia or schizoaffective disorder. First, among the wide-
correlated with the SRH across subjects (P50.001, r = 0.63 and spread neuronal network of AVH-related activations, the signals
P50.001, r = 0.73 for the whole group, and P = 0.001 and from the bilateral IFG correlated strongly with the SRH, indepen-
P = 0.013 for the 7 subjects with schizophrenia, respectively; dently of the subjective interpretation style, loudness of AVHs and
values for the most significantly correlated voxels reported the dose of antipsychotic medication.
throughout; Fig. 2 and Supplementary Table 4). This correlation The motor theory of speech perception assumes the compre-
was statistically significant (P50.05) both with and without con- hension of external speech to rely on subliminal matching to the
founding covariates that included dopamine-2-receptor blocking listener’s own articulatory gestures (Liberman and Whalen, 2000).
medication, self-certainty ratings, and the subjective loudness of This matching probably relies on the IFG pre-motor speech-pro-
the AVH. The strength of the AVH-related IFG activation duction area that is activated also during speech comprehension;
showed a trend towards explaining better (z = 1.2, P = 0.12) for a review, see Nishitani et al. (2005). Although imaging studies
the individual SRH than did the strength of any AVH- of AVHs have focused on auditory cortices (Allen et al., 2008), our
related activation in the temporal lobe, including the auditory findings converge with theoretical literature (Atkinson, 2006) and
cortices. with recent imaging findings with a larger subject group (Sommer
et al., 2008) to suggest that the IFG correlates of the SRH com-
Correlation of the hallucination-specific prise the perceptual key substrate for AVHs.
In addition to speech comprehension, the IFG is involved in the
coupling of the IFG with the SRH production of overt and inner speech, as well as in the imagination
At the group level, no statistically significant differences were of the speech of others (McGuire et al., 1996; Liberman and
found in the coupling of the IFG with other brain regions during Whalen, 2000; Nishitani et al., 2005). Therefore, additional brain
AVH-periods versus non-AVH periods (‘AVH-related coupling’, circuits are likely to contribute to differentiation between self-
P40.005 in the regions of interest, uncorrected, or P40.05 in produced and externally triggered verbal material (Jeannerod
other brain regions, corrected for multiple comparisons). and Pacherie, 2004). We expected neuronal substrates for this
The SRH variability explained the inter-individual variation of the distinction to include cortical midline regions related to self-
AVH-related coupling: The SRH scores correlated positively with monitoring (Northoff and Bermpohl, 2004). Accordingly, the
the AVH-related coupling between the left IFG and the following SRH correlated negatively with the AVH-related coupling of
brain regions: the bilateral supratemporal auditory cortex the IFG with the pregenual and posterior cingulate cortex.
(P = 0.004, r = 0.40 for the left and P = 0.024, r = 0.34 for the The decreased coupling could reflect the poor controllability of
right hemisphere), the right posterior temporal lobe (P = 0.008, AVHs that is likely to be associated with the SRH. This interpretation
r = 0.24), the middle right anterior cingulate cortex (P = 0.001, agrees with the finding that the function of the medial prefrontal
r = 0.18), the right ventral striatum and the left nucleus accumbens cortex near the pregenual cingulate cortex is compromised when
(P = 0.004, r = 0.15 and P = 0.001, r = 0.21, respectively; Fig. 3, subjects with schizophrenia attribute words as self-generated or
Supplementary Table 5). The correlation of the SRH with the cou- as generated by the experimenter (Vinogradov et al., 2008).
pling between the left IFG and the left auditory cortex was stron- Our analysis of the coupling of the IFG aimed further to test the
gest in the Heschl’s gyrus, within 1 cm of the maximum activation hypotheses about association of the SRH with the agency-related
elicited by brief tones in the same subjects (x, y, z = –51, –15, 8 and the salience-detection-related circuitries that have been
versus –55, –12, 1, respectively). The SRH values correlated suggested to contribute to reality distortion (Kapur, 2003; Frith,
positively also with the coupling of the right IFG with the right 2005). Supporting the first hypothesis, SRH scores correlated
posterior superior temporal gyrus (x, y, z = 59, –26, 26; P50.001). positively with the coupling of the IFG with the middle anterior
These positive correlations were statistically significant both in the cingulate cortex and the right posterior temporal lobe. The middle
entire subject group and in the subgroup with schizophrenia anterior cingulate cortex has been implicated in the experience of
(Supplementary Table 5) and they remained significant with the agency in healthy subjects (Tomlin et al., 2006) and in misattribu-
application of global normalization in the reanalysis (P50.05). tion of own recorded speech as others’ speech in schizophrenic
The SRH values correlated negatively with the AVH-related cou- subjects (Allen et al., 2007) and the right posterior temporal lobe
pling between the left IFG and the left pregenual and posterior has been implicated in the experience of agency (Tankersley et al.,
cingulate cortex (P50.001, r = –0.57 and P = 0.003, r = –0.65, 2007).
respectively; Fig. 4, Supplementary Table 6) as well as with the During treatment with antipsychotic drugs, the reduction in
AVH-related coupling between the right IFG and the left reality-distortion-related positive symptoms correlates with the
3000 | Brain 2009: 132; 2994–3001 T. T. Raij et al.
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Funding Gitelman DR, Penny WD, Ashburner J, Friston KJ. Modeling regional and
psychophysiologic interactions in fMRI: the importance of hemody-
This study benefited from the financial support of the Academy of namic deconvolution. Neuroimage 2003; 19: 200–7.
Finland (National Centres of Excellence Programme 2006–2011), Hoffman RE, Hampson M, Wu K, Anderson AW, Gore JC, Buchanan RJ,
ERC Advanced Grant #232946, the Ella and Georg Ehrnrooth et al. Probing the pathophysiology of auditory/verbal hallucinations by
combining functional magnetic resonance imaging and transcranial
Foundation, the Finnish Medical Foundation, the Jalmari and
magnetic stimulation. Cereb Cortex 2007; 17: 2733–43.
Rauha Ahokas Foundation, and the Finnish Psychiatric Research Hubl D, Koenig T, Strik W, Federspiel A, Kreis R, Boesch C, et al.
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Hunter MD. Locating voices in space: a perceptual model for auditory
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