An evoked auditory response fMRI study of the effects of rTMS on putative AVH pathways in healthy volunteers

Neuropsychologia 48 (2010) 270–277

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An evoked auditory response fMRI study of the effects of rTMS on putative AVH pathways in healthy volunteers D.K. Tracy a,∗ , O. O’Daly a , D.W. Joyce a , P.G. Michalopoulou a , B.B. Basit a , G. Dhillon a , D.M. McLoughlin b , S.S. Shergill a,c a b c

CSI Lab, Department of Psychological Medicine, The Institute of Psychiatry, King’s College London, UK Dept of Psychiatry & Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland The Wellcome Department of Imaging Neuroscience, The Institute of Neurology, University College London, UK

a r t i c l e

i n f o

Article history: Received 17 February 2009 Received in revised form 31 July 2009 Accepted 14 September 2009 Available online 19 September 2009 Keywords: TMS Auditory hallucinations fMRI

a b s t r a c t Background: Auditory verbal hallucinations (AVH) are the most prevalent symptom in schizophrenia. They are associated with increased activation within the temporoparietal cortices and are refractory to pharmacological and psychological treatment in approximately 25% of patients. Low frequency repetitive transcranial magnetic stimulation (rTMS) over the temporoparietal cortex has been demonstrated to be effective in reducing AVH in some patients, although results have varied. The cortical mechanism by which rTMS exerts its effects remain unknown, although data from the motor system is suggestive of a local cortical inhibitory effect. We explored neuroimaging differences in healthy volunteers between application of a clinically utilized rTMS protocol and a sham rTMS equivalent when undertaking a prosodic auditory task. Method: Single-blind placebo controlled fMRI study of 24 healthy volunteers undertaking an auditory temporoparietal activation task, who received either right temporoparietal rTMS or sham RTMS. Results: The main effect of group was bilateral inferior parietal deactivation following real rTMS. An interaction of group and task type showed deactivation during real rTMS in the right superior temporal gyrus (STG), left thalamus, left postcentral gyrus and cerebellum. However, the left parietal lobe showed an increase in activation following right sided real rTMS, but this increase was specific to a non-linguistic, tone-sequence task. Conclusion: rTMS does cause local inhibitory effects, not only in the underlying region of application, but also in functionally connected cortical regions. However, there is also a related, task dependent, increase in activation within selected cortical areas in the contralateral hemisphere; these are likely to reflect compensatory mechanisms, and such cortical activation may in some cases contribute to, or retard, some of the therapeutic effects seen with rTMS. © 2009 Elsevier Ltd. All rights reserved.

1. Introduction Auditory verbal hallucinations (AVH), are the most prevalent symptom in patients with schizophrenia, and are resistant to standard pharmacological treatment in approximately 25% of patients (Shergill, Murray, & McGuire, 1998). Transcranial magnetic stimulation (TMS) is a new and relatively non-invasive tool demonstrated to have a beneficial effect on AVH (Fitzgerald, Benitez, & Daskalakis, 2006; Hoffman, Gueorguieva, & Hawkins, 2005; Hoffman, Hawkins, & Gueorguieva, 2003; Lee, Kim, & Chung, 2005). These studies have

∗ Corresponding author at: Box 45, Department of Psychological Medicine, The Institute of Psychiatry, King’s College London, London SE5 8AF, UK. Tel.: +44 2078480029; fax: +44 2078480350. E-mail address: [email protected] (D.K. Tracy). 0028-3932/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2009.09.013

employed 1 Hz (low frequency) repetitive TMS (rTMS), a protocol designed to reduce underlying cortical excitability (McIntosh, Semple, & Tasker, 2004), applied over cortical regions shown to be activated in functional imaging studies of AVH (Tracy & Shergill, 2006). Most of these rTMS studies have targeted the left temporoparietal cortex (Hoffman et al., 2005, 2003), but more recent studies targeting the right temporoparietal cortex have also reported similar results. Lee et al. (2005) demonstrated that both left and right temporoparietal rTMS showed significant reductions in PANSS positive symptom and Clinical Global Impressions (CGI) scores relative to the sham condition, although there were no significant differences between the three groups in reducing AVH frequency. However, a meta-analysis (Aleman, Sommer, & Kahn, 2007) found the opposite, that rTMS lessened AVH but did not have more generalizable effects on other psychotic symptoms. Not all studies have reported positive results, with McIntosh et al. (2004),

Table 1 Summary of recent clinical trials evaluating the effectiveness of rTMS in reducing auditory verbal hallucinations. Site

N

Design

Protocol/treatment

Drug controlled ?

Scales/ measures

Result

Brunelin et al. (2006)

Left temporal (T3-P3)

14/10 DB

1 Hz, 90% MT

2 × 1000 pulses per day; 5 consecutive days

Yes

AHRS SAPS

Significant improvement in AHRS for treatment group vs. sham

Chibbaro et al. (2005)

Left temporal (T3-P3)

8/8 DB

1 Hz, 90% MT

1 × 900 pulses per day; 4 consecutive days

Yes

SAPS, SAH and SANS improved at 1, 2 and 3 weeks follow-up vs. sham

Hoffman et al. (2005)

Left temporal (T3-P3)

27/23 DB

1 Hz, 90% MT

Day 1: 480 pulses Day 2: 720 Days 3–10: 960 10 days exc. weekends

Yes

SAPS SANS SAH HCS AHRS CGI PANSS

Lee et al. (2005)

Left or right temporal (T3-P3)

1 Hz, 100% MT

1200 pulses per day; 10 consecutive days

No

Left temporal (T3-P3)

1 Hz, 90% MT

2 × 1000 pulses per day; 5 consecutive days

Yes

AHRS CGI PANSS AHRS

Left or right rTMS: improvement in CGI vs. sham.

Poulet et al. (2005)

McIntosh et al. (2004)

Left temporal (T3-P3)

1 Hz, 80% MT

Day 1: 240 pulses Day 2: 480 Day 3: 720 Day 4: 960

Yes

PANNS AVLT

No difference between sham and active conditions on any scales

Hoffman et al. (2003)

Left temporal (T3-P3)

13L/7a 12R/7 DB 10–5 sham then active; 5 active then sham; 1 week washout DB 16 – 8 sham then active; 8 active then sham; 1 week washout DB 12/12 DB

1 Hz, 90% MT

Yes

HCS CGI PANSS

HCS scores show significant improvement vs. sham

Case report

1 Hz 90% MT

Day 1: 480 pulses Day 2: 720 Day 3–10: 960 10 days exc. weekends 9519 s over 2 weeks; non-consecutive sessions and each session variable

Yes

SAPS

Significant decrease in SAPS over 2 months

Franck et al. (2003)

Significant improvement in HCS at day 9 vs. sham. Frequency of hallucinations (AHRS) significantly improved vs. sham.

Significant effect of rTMS on AHRS scores vs. sham

D.K. Tracy et al. / Neuropsychologia 48 (2010) 270–277

Study

Site: parentheses indicate EEG electrode sites (in the 10-20 system) used as references points for locating stimulating coil. N: active/sham; DB: double blind allocation was used. Design: %MT, percentage of motor threshold. Drug control: if medication history or levels were explicitly stated. Scales/measures: AHRS, Auditory Hallucinations Ratings Scale; SAPS, Scale for Assessment of Positive Symptoms; SANS, Scale for Assessment of Negative Symptoms; SAH, severity of auditory hallucinations; HCS, Hallucination Change Scale; CGI, clinical global impressions; PANSS, Positive and Negative Syndrome Scale; AVLT, Auditory and Verbal Learning Test (Saba, Schurhoff, and Leboyer) review the major findings of rTMS used as a treatment for schizophrenia symptoms, focusing on controlled trials of various protocols on the DLPFC. a Lee et al. (2005) define a treatment group of 13 with 7 sham for the left temporoparietal group and 12 treatment and 7 sham for right temporoparietal.

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applying rTMS to the left temporoparietal cortex and failing to establish significant improvement in AVH: however it should be noted that in this trial the rTMS was interrupted every minute of each stimulation for 15 s, which may have reduced the effects of the RTMS. More recent work (Fitzgerald et al., 2006) has suggested that follow-up rTMS upon relapse of AVH, after initial treatment, may be a successful strategy. Table 1 contains a summary of rTMS clinical trials to treat AVH since 2003. Overall, variability in patient symptoms, concomitant medication and different experimental paradigms may contribute to the lack of consistent results. Therefore, it may be useful to clarify the functional cortical effects of this low frequency rTMS paradigm, and functional magnetic resonance imaging offers an opportunity to do this. Understanding the neural effects in healthy controls is an essential prerequisite in examining the mechanism of any therapeutic effects in a patient cohort. Our own imaging data in hallucinating patients has suggested a prominent role of the right temporoparietal cortex in the aetiology of AVH (Shergill, Brammer, & Williams, 2000), supported by other neuroimaging data (Dierks, Linden, & Jandl, 1999; Sommer, Ramsey, & Kahn, 2001; Weiss, Hofer, & Golaszewski, 2006; Woodruff, Wright, & Bullmore, 1997), which guided our choice of this side for application of the rTMS. This region has been implicated in prosodic processing (Borod, Andelman, & Obler, 1992; Pell, 1999; Ross & Mesulam, 1979; Shah, Baum, & Dwivedi, 2006; Wunderlich, Ziegler, & Geigenberger, 2003), which is a key component of AVH. Prosody comprises the non-verbal aspects of speech (Ross, 1993), and abnormal prosodic processing has been demonstrated in schizophrenia (Bozikas, Kosmidis, & Anezoulaki, 2006; Frith & Done, 1988; Matsumoto, Samson, & O’Daly, 2006; Mitchell & Crow, 2005; Murphy & Cutting, 1990), and correlated specifically with AVH (Matsumoto et al., 2006). In this study, based on our previous neuroimaging findings, we used a contralateral variation on most commonly used rTMS protocol for treating AVH (Hoffman et al., 2005), applied over the right temporoparietal cortex in healthy participants whilst performing a prosodic pitch processing task. The task used different matched verbals and tone sequences stimuli to examine the effect of differential functional demands within the left and right temporoparietal cortices respectively. We hypothesised that low frequency rTMS would produce generalized suppression of the right temporoparietal cortex underlying the area of application, with related attenuation in regions such as the ipsilateral prefrontal cortex which are recognised to have significant anatomical and functional connectivity with this region. 2. Methods and materials 2.1. Participants Twenty-four healthy participants were recruited through advertisements in a city-wide newspaper. Inclusion criteria were: males aged between 18 and 55, righthandedness, English as a first language. Exclusion criteria were: previous psychiatric or neurological illness, hearing or speech impairment, illicit drug use in the previous 6 months and routine contraindications to MRI scanning. All participants provided written informed consent, their mean age was 31 years (SD = 9.6), all participants had completed secondary education and none had any formal training in playing musical instruments. The study had been approved by the local research ethics committee (South London and Maudsley NHS Trust). Participants were randomised into either the active and sham arm of the study, with twelve in each group. Participants were blind as to their group assignment. There were no significant differences between groups in terms of age or education. 2.2. rTMS rTMS was applied using the Magstim Super Rapid stimulator (Magstim Co. Ltd, UK) with a figure-of-eight coil. Participants were comfortably seated, and motor thresholds (MT) in the abductor pollicis brevis muscle of the left hand were established by visual inspection for all (both the active and sham groups) by the application of rTMS to the right motor cortex. A MT is a synchronous muscle response evoked by a TMS pulse stimulating the motor cortex, and the lowest magnetic field required to induce this is known as the motor threshold (Haraldsson, Ferrarelli,

& Kalin, 2004). Motor thresholds are reasonably stable within individuals (Mills & Nithi, 1997). Following the protocol previously used by Hoffman, Boutros, and Hu (2000), either active (at 90% of MT) at 1 Hz or sham rTMS was applied to the temporoparietal junction, deemed to be 5 cm posterior and 2 cm inferior to the abductor pollicis brevis site for 16 min. Sham rTMS utilized a purpose-built coil (Magstim Co. Ltd, UK) that looks identical to the real coil but which did not deliver a magnetic field. 2.3. Prosodic stimuli and materials A modified English version of the music and prosody discrimination task designed by Patel, Peretz, and Tramo (1998) was used in this study. The stimuli consisted of lexically matched sentence pairs and their non-verbal, tone sequence analogues. Tone sequence stimuli were created by converting each sentence into a tone sequence which corresponded with the sentence’s fundamental frequency in pitch and timing; a detailed description is available in Patel et al. (1998). The only prosodic changes in stimuli utilized in this experiment were in internal pitch pattern (emphasis shift) as our previous work (Matsumoto et al., 2006) had found internal pitch changes to be the most sensitive to subtle neurological deficits. The task consisted of six counterbalanced blocks. Each block was composed of twelve trials comprising four pairs of sentences, four pairs of tone sequences, and four null trials (a silent period equal in length to four paired stimuli) presented in random order. Each trial consisted of a pair of stimuli separated by a 1 s interval. The pair of stimuli differed in the pitch of an internal component in 50% of trials. Stimuli pairs had an average length of 5036 ms. Following a visual cue at the end of each trial, participants indicated whether the paired stimuli were the same or different by using their right index finger and a button press. The total length of the six counterbalanced blocks was 17 min 39 s. Pilot work suggested that participants experienced greater difficulty in same paired stimuli compared with different pairs, as they reported actively having to attend to the entire length of the sequence during the same pairs’ comparison. 2.4. Behavioural analysis We looked at the relationship between treatment (sham and real rTMS) and the two task related factors – modality (sentence and tone sequence) and type (same and different) – using a repeated measures ANOVA. Separate ANOVAs examined the effect of these factors in relation to reaction time and accuracy rates. The identification of significant main effects or interactions was followed by post hoc t-tests to clarify the relationships. All analyses were carried out with SPSS. 2.5. fMRI acquisition Participants were scanned within 10 min of the application of the real or sham rTMS. Gradient echo echoplanar imaging (EPI) data were acquired on a neurooptimised GE Signa 1.5 Tesla system (General Electric, Milwaukee, WI, USA) at the Maudsley Hospital, London. A quadrature birdcage headcoil was used for radio frequency transmission and reception. Foam padding was placed around the participant’s head in the coil to minimize head movement. One hundred and forty four T2*-weighted whole-brain volumes depicting blood oxygen level-dependent (BOLD) contrast were acquired at each of 24 near-axial non-contiguous planes parallel to the intercommissural (AC-PC) line (slice thickness = 5 mm; gap = 0.5 mm; TR = 2.1 s; echo time = 40 ms; flip angle = 90◦ ; matrix = 64 × 64). This EPI data set provided complete brain coverage. At the same session, a high-resolution gradient echo image of the whole brain was acquired in the intercommissural plane consisting of 43 slices (slice thickness = 3 mm; gap = 0.3 mm; TR = 3 s; flip angle = 90◦ ; matrix = 128 × 128). Scanner noise during stimuli presentation was minimized by using a partially silent acquisition (Amaro, Williams, & Shergill, 2002) during the stimuli presentation lasting 6.3 s whilst fMRI data (associated with prominent scanner noise) was collected during the following 8.4 s. 2.6. fMRI analysis The data were first realigned (Bullmore, Brammer, & Rabe-Hesketh, 1999) to minimize motion related artifacts and smoothed using a Gaussian filter (FWHM 7.2 mm). Responses to the experimental paradigm trial were then detected by timeseries analysis using Gamma variate functions (peak responses at 4 and 8 s) to model the BOLD response. The analysis was implemented as follows. First, in each experimental condition, trial onsets were modeled as stick-functions which were convolved separately with the 4 and 8 s Poisson functions to yield two regressors of the expected haemodynamic response to that condition. The weighted sum of these two convolutions that gave the best fit (least-squares) to the time series at each voxel was then computed. This weighted sum effectively allows voxel-wise variability in time to peak haemodynamic response. Following this fitting operation, a goodness of fit statistic was computed at each voxel. This was the ratio of the sum of squares of deviations from the mean intensity value due to the model (fitted time series) divided by the sum of squares due to the residuals (original time series minus model time series). This statistic is called the SSQratio. In order to sample the distribution of SSQratio under the null hypothesis that observed values of SSQratio were not determined by experimental design (with minimal assump-

D.K. Tracy et al. / Neuropsychologia 48 (2010) 270–277 tions), the time series at each voxel was permuted using a wavelet-based resampling method described in detail in Bullmore, Long, and Suckling (2001). This process was repeated 10 times at each voxel and the data combined over all voxels, resulting in 10 permuted parametric maps of SSQratio at each plane for each participant. The same permutation strategy was applied at each voxel to preserve spatial correlational structure in the data during randomisation. Combining the randomised data over all voxels yields the distribution of SSQratio under the null hypothesis. Voxels activated at any desired level of type I error can then be determined obtaining the appropriate critical value of SSQratio from the null distribution. For example, SSQratio values in the observed data lying above the 99th percentile of the null distribution have a probability under the null hypothesis of ≤0.01. It has been shown that this permutation method gives very good type I error control with minimal distributional assumptions (Bullmore et al., 2001). In order to extend inference to the group level, the observed and randomised SSQratio maps were transformed into standard space by a two stage process involving first a rigid body transformation of the fMRI data into a high-resolution inversion recovery image of the same participant followed by an affine transformation onto a Talairach template (Brammer, Bullmore, & Simmons, 1997). By applying the two spatial transformations computed above for each participant to the statistic maps obtained by analyzing the observed and wavelet-randomised data, a generic brain activation map (GBAM) could be produced for each experimental condition by testing the median observed SSQratio over all participants at each voxel (median values were used to minimize outlier effects) at each intracerebral voxel in standard space (Talaraich, 1988) against a critical value of the permutation distribution for median SSQratio ascertained from the spatially transformed wavelet-permuted data (Brammer et al., 1997). In order to increase sensitivity and reduce the multiple comparison problem encountered in fMRI, hypothesis testing was carried out at the cluster level using the method developed by Bullmore et al. (1999), shown to give excellent cluster-wise type I error control in functional fMRI analysis. When applied to fMRI data, this method estimates the probability of occurrence of clusters under the null hypothesis using the distribution of median SSQratios computed from spatially transformed data obtained from wavelet permutation of the time series at each voxel (see above). All analyses were performed with <1 false positive clusters expected per image, under the null hypothesis. Finally, we employed a 2 × 2 factorial design to examine the interaction of participant group (real or sham rTMS) with the variables of task type (sentence or tone sequence) in order to determine regional effects of rTMS. The SSQ values were plotted for regions demonstrating significant interaction effects.

3. Results 3.1. Behavioural data All 24 participants successfully completed both the rTMS and fMRI elements of the experiment. No side effects were reported to the rTMS. When exploring response time and accuracy, using a repeated measure ANOVA, we failed to identify any effects or interactions between the three factors of interest—group, stimulus type and modality.

273

Table 3 Areas of activation in the top half of Fig. 2. Hem: hemisphere, BA: Brodman’s area. Size

Talairach coordinates

66 28

X

Y

Z

51 36

11 22

−2 −13

Hem

BA

Cerebral region

R R

22 47

Superior temporal gyrus Inferior frontal gyrus

Table 4 Areas of activation in the bottom half of Fig. 2. Hem: hemisphere, BA: Brodman’s area. Size

Talairach coordinates

99 47

X

Y

−58 0

−44 −22

Hem

BA

Cerebral region

L L

21

Middle temporal gyrus Thalamus

Z −2 4

Table 5 Areas of activation in Fig. 3. Hem: hemisphere, BA: Brodman’s area. Size

Talairach coordinates Hem X

Y

Z

213 196 187 59 59

−58 33 47 51 0

−22 −56 −48 7 −22

20 −29 31 −13 4

L R R R L

BA

Cerebral region

40

Postcentral gyrus Anterior lobe, cerebellum Supramarginal gyrus, parietal lobe Superior temporal gyrus Thalamus

40 38

values were plotted. rTMS resulted in generalized inhibition of right STG and right parietal lobe activation in both tone sequence and sentence tasks (Fig. 4): although these regions showed greater activation during the tone task in those receiving sham rTMS (i.e. normal cerebral activation), and greater activation during the sentence task after real rTMS, the effect of real rTMS on the different tasks was not statistically significant in these regions. The thalamus and cerebellum were more active in sentence than tone-sequence tasks in healthy volunteers receiving sham rTMS. rTMS inhibited both regions, regardless of task type, leading to a loss of task differentiation. In the left parietal lobe, those receiving sham rTMS show little differentiation in activation between sentence and tonesequence tasks. Following rTMS however, there is a decrease in activation during the sentence task, but an increase in activation during the tone-sequence task (Fig. 5).

3.2. Neuroimaging data The main effect of group is shown in Fig. 1, with decreased activation in the bilateral inferior parietal lobes (Table 2) after real rTMS (compared with sham rTMS) regardless of the task. The main effect of task is shown in Fig. 2, with the tone-sequence task preferentially activating the right superior temporal gyrus and the inferior frontal gyrus (Table 3; top half, Fig. 2); whilst the sentence task preferentially activates the left middle temporal gyrus and thalamus (Table 4; bottom half, Fig. 2). Significant interactions were observed in the right parietal lobe, right superior temporal gyrus (STG), left thalamus, left parietal postcentral gyrus and cerebellum (Fig. 3; Table 5). To clarify the influence of group on stimulus type, the mean SSQ value was extracted from each cluster in each individual, and the median Table 2 Areas of activation in Fig. 1. Hem: hemisphere, BA: Brodman’s area. Size

108 92

Talairach coordinates X

Y

Z

−54 36

−33 −44

26 42

Hem

BA

Cerebral region

L R

40 40

Inferior parietal lobe Inferior parietal lobe

4. Discussion Behavioural results failed to show any statistically significant differences between the real and sham rTMS groups in accuracy or timing. This general lack of behavioural differences and the neuroimaging changes suggest there is a significant cortical reserve in the affected region, even with attenuated activation, or that other regions may be able to function to compensate for this. The factorial analysis showed decreased bilateral inferior parietal activation after the rTMS regardless of task type (Fig. 1; Table 2). We observed the predicted attenuation in the rTMS group following inhibitory rTMS to the right temporoparietal junction, but also in the homologous left-sided region, commensurate with results of high frequency rTMS by Bestmann, Baudewig, and Siebner (2005). This bi-parietal deactivation following rTMS may explain why some studies have failed to show any differences between right and left application of rTMS (Lee et al., 2005; McIntosh et al., 2004). Following both real and sham rTMS, the tone-sequence task led to relatively greater activation in the right inferior frontal gyrus and superior temporal gyrus (STG) compared with the sentence task (Fig. 2, top half; Table 3). Conversely, the sentence task preferentially activated left hemispheric regions of the middle temporal

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Fig. 1. The main effect of group (real rTMS/sham rTMS): ascending transverse sections through the brain from left to right, with the right side of the brain shown in the left side of each image, illustrating regions of generic brain activation associated with decreased activation in the real rTMS group, regardless of the task. Table 2 describes the activation.

Fig. 2. The main effect of task (sentence/tone): two sets of ascending transverse sections through the brain from left to right, with the right side of the brain shown in the left side of each image. The top three slices illustrate regions of generic brain activation associated with the tone sequence, whilst the bottom three slices illustrate regions associated with the sentence task and they are described by Tables 3 and 4 respectively.

Fig. 3. Interaction effects: ascending transverse sections through the brain from left to right, with the right side of the brain shown in the left side of each image, illustrating regions of generic brain activation associated with an interaction between group (real, sham rTMS) and the task (sentence, tone). Table 5 describes the activation.

gyrus and thalamus (Fig. 2, bottom half; Table 4), regardless of group: both of these task dependent findings in accordance with previous imaging data of prosodic comprehension (Buchanan, Lutz, & Mirzazade, 2000; George, Parekh, & Rosinsky, 1996; Imaizumi, Mori, & Kiritani, 1997; Wildgruber, Hertrich, & Riecker, 2004; Wildgruber, Pihan, & Ackermann, 2002). Significant interactions of treatment group and stimulus types were observed in five regions: the right parietal lobe, the right STG, the cerebellum, the thalamus and the left parietal lobe (Fig. 3; Table 5). The right parietal lobe site was the region directly underneath the rTMS site; as anticipated, rTMS inhibited this underlying region, with relatively greater – though not statistically significant – attenuation during processing of the tone-sequence task (Fig. 4). The right STG showed increased activation during the tone-sequence task relative to the sentence task. rTMS inhibited activation in this region, affecting both tasks equally. The right STG and right parietal lobe show expected non-specific inhibitory

Fig. 4. The effects of rTMS task on task-sensitive activation in the right parietal cluster identified in the interaction analysis. Activation is represented by the sum of squares quotient (SSQ) shown in the Y-axis, with task conditions (sentence and tone sequence) shown on the x-axis.

D.K. Tracy et al. / Neuropsychologia 48 (2010) 270–277

Fig. 5. The effects of rTMS task on task-sensitive activation in the left parietal cluster identified in the interaction analysis. Activation is represented by the sum of squares quotient (SSQ) shown in the Y-axis, with task conditions (sentence and tone sequence) shown on the x-axis. Whilst this region was not significantly modulated by task conditions at baseline (sham rTMS), following rTMS this region was significantly more active in response to tonal sequences as compared to spoken sentences, with the sentence task showing a small decrease in activation relative to the sham rTMS.

effects, as might be predicted by the application of low frequency rTMS. The greater activation in the cerebellum and thalamic regions during the lexical task, as opposed to the tone-sequence task, in those who did not receive rTMS might be predicted given known involvement of these regions in language processing (Booth, Wood, & Lu, 2007). The effects of real rTMS were similar in both regions, and slow, inhibitory rTMS may be acting downstream via corticothalamic and cortico-cerebellar fibres (Kimura, Minamimoto, & Matsumoto, 2004; Ramnani, 2006) to decrease activation in these regions. The subsequent apparent loss of task differentiation might be explained by the generally low level of activation post-rTMS. The results in the left parietal lobe are perhaps the most interesting. The parietal lobes have been postulated as working memory stores for prosodic tasks. The non-specific inhibitory effects of slow rTMS on the directly stimulated right parietal lobe were anticipated, following neuroimaging of rTMS on the visual cortex (Boroojerdi, Prager, & Muellbacher, 2000). However, contralaterally, whilst there is inhibition during the sentence task, there is increased activation during the tone-sequence task (Fig. 5). A possible explanation is that as the right hemispheric semantic prosodic-pitch network is inhibited by rTMS, the homologous region of the left parietal lobe compensated with specific task related increases in activity. This suggests that the left-sided region is specialised for language but has the ability to compensate when required for right sided processes (Baldo & Dronkers, 2006). The absence of any decrements in behavioural performance may also reflect compensatory change. Similar changes have been observed in language related function in recovery of function after brain damage (Voets, Adcock, & Flitney, 2006). Andoh and Martinot (2008) suggest that a similar model of interhemispheric compensation might explain some of the therapeutic effects of rTMS, with a functional reorganisation in the contralateral homologue. Work by Nahas, Lomarev, and Roberts (2001) has shown rTMS to cause transient cortical activation whilst participants performed a cognitive task, though as this was in a design utilizing fMRI interleaved with 1 Hz rTMS, such results are likely to be due to the immediate effects of neuronal depolarization and firing, with deactivation expected regarding sustained long term depotentiation effects. Speer, Kimbrell, and Wassermann (2000) demonstrated that rTMS can affect contralateral regional cerebral blood flow, though their work, in depressed patients receiving left prefrontal cortex rTMS, only showed increased activity during fast (20 Hz) rTMS, with decreases noted for slow (1 Hz) rTMS. This did not, in either case, show any lateral differentiation in activation as has been reported in this present work. In summary, rTMS may exert its therapeutic effects on AVH through both

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local decreases underlying the coil but also through increased activation of homologous regions and normalizing aspects of prosodic functioning. rTMS studies involving AVH have tended to focus on clinical outcome measures, measured for example with hallucinatory scales. One study has explored the effects of left temporoparietal rTMS (1 Hz for 1000 s over 10 daily applications) versus sham on 24 schizophrenic patients with treatment refractory AVH and reported improvement during a source monitoring task (Brunelin, Poulet, & Bediou, 2006). A number of studies have combined fMRI and rTMS, though they have tended to focus on stimulatory high frequency rTMS, and they have demonstrated increased activation over the motor cortex where rTMS was applied, and also in regions with strong anatomical connections (Baudewig, Siebner, & Bestmann, 2001; Bohning, Shastri, & Nahas, 1998; Bohning, Shastri, & Wassermann, 2000). 5. Limitations We only examined right handed males which limits the generalizability of the findings. However, both handedness and gender may affect the neural structures involved in the processing of language (Hagmann, Cammoun, & Martuzzi, 2006) and prosody (Rymarczyk & Grabowska, 2006), and thus these exclusion criteria removed this confounder. There is concern about the lack of a reliable placebo control in rTMS studies (Haraldsson et al., 2004). Ways around this include tilting the coil away from the head in sham participants, or the utilization of a sham coil. In both cases there are difficulties: an ideal sham condition should evoke the same physical sensation in the participant, such as scalp twitches, and both participant and experimenter should be blinded to the treatment arm. The former does not occur with either method, though blinding the experimenter to the treatment arm is possible with a sham coil. It has been shown that tilting the coil may induce activation within the cortex (Lisanby, Luber, & Perera, 2000), and on balance, we felt that a sham coil was preferable. We utilized a real coil in all individuals to find the MP. Thus all participants received at least some real rTMS. Therefore participants, having received both real and sham rTMS might be in a position to differentiate them, removing the blinding of the study. We asked participants to state whether they thought they had had the active or sham treatment, and there was no correlation between their answers and the actual treatment given. Furthermore, we felt this avoided the confounder of results possibly being ascribed as due solely to the initial rTMS over the motor cortex, which could be argued if the sham group did not receive this part of the protocol. The protocol of 16 min of 1 Hz rTMS fits with Haraldsson et al.’s (2004) notion of rational design for rTMS protocol and accords with the most commonly used regime for treatment of AVH: however, our study utilized a single session of rTMS, whereas clinically it is usual to receive multiple sessions of such stimulation. It would therefore be important to follow-up our work with neuroimaging of longer-term rTMS, to more accurately determine the changes that follow actual clinical practice. There was a mean delay of approximately 10 min between the end of rTMS and commencement of fMRI, presenting the problem of loss of rTMS effect. However it could be argued that this strengthens the evidence for the data that remain. Furthermore there is evidence for the persistence of rTMS effects (Ben-Shachar, Gazawi, & Riboyad-Levin, 1999; Chen, Classen, & Gerloff, 1997; Fitzgerald, Brown, & Daskalakis, 2002; Knecht, Sommer, & Deppe, 2005). Coil placement, although following on previous work, is probabilistic in nature (Li, Nahas, & Kozel, 2004), and this has been shown to stimulate a wide range of Brodman locations depending upon the participant’s head size (Herwig, Schonfeldt-Lecuona, & Wunderlich, 2001). Whilst less accurate than fMRI-guided stimulation, there is no clear difference between such functionally guided

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TMS and the other common probabilistic method based on the 1020 EEG system (Sparing, Buelte, & Meister, 2008). The imaging data provide face validity that stimulation was applied consistently over the same cortical region within the participants, as attenuation was evident over the area underlying the coil in all of the participants. The magnitude of rTMS-induced changes depends on several extrinsic factors such as intensity and frequency of the rTMS, the number of treatment sessions and the length of individual sessions. Additionally, intrinsic factors (Burt, Lisanby, & Sackeim, 2002) include the functional state of the cortex targeted by rTMS (Siebner & Rothwell, 2003). TMS has also been shown to alter gene expression independent of magnetic stimulus direction, or the integrity of neural circuitry in brain slices (Ji, Schlaepfer, & Aizenman, 1998), and such effects may be linked to long term neuroplastic effects linked to prolonged therapeutic benefits. 6. Conclusions Pitch processing involves a bilateral network of temporal and parietal regions. Low frequency rTMS applied to the right temporoparietal border inhibits neural function locally and within anatomically connected regions. However, a double dissociation was evident within activation in the left parietal lobe, which showed simultaneous inhibition during the sentence task but increased activation during the tone sequence processing task. Research on the effects of rTMS in the treatment of AVH has produced varying results. There is no agreement on the parameters of a suitable protocol, with variations in the criteria of patient selection, site and length of application, duration of protocol and outcome measurements. Most trials utilize only clinical outcomes and do not have healthy controls. Our evidence of post-rTMS bilateral deactivation, albeit task specific, may explain the finding in some research of a lack of any statistically significant differences between left and right temporoparietal rTMS (Lee et al., 2005). Our previous data (Shergill et al., 2000), found that only four out of six individual participants showed prominent right temporal activation whilst hallucinating. This suggests that the lack of consistent efficacy in rTMS studies may reflect variability in patient selection. The content of the hallucination, whether more emotional, with a higher prosodic content, or whether more semantic in nature, may affect outcome of, or determine the optimal site for rTMS application. Prosodic deficits in schizophrenia are well established, and it has been postulated that such deficits may contribute to misattribution in auditory hallucinations (Cutting, 1990): however, to the best of our knowledge, such subdivision of hallucination subtype is not an area which has been adequately explored in the neuroimaging literature to date. Future work could use fMRI to clarify the regions of maximal activation during AVH for a given individual and subsequently apply rTMS specifically over site(s) of maximal activation. fMRI as a tool has the obvious benefit of allowing multiple follow-up scans to monitor cerebral changes prospectively. To our knowledge, this is the first study to use fMRI to assess the cerebral changes post-rTMS in the postulated AVH network. It is clear that the effects of inhibitory rTMS are complex, and can result in either stimulatory or compensatory effects, even within the same cerebral region, and apparent compensatory contralateral activation may indeed counteract as well as produce therapeutic benefit. TMS works by local attenuation of cortex underlying the TMS coil, but also enhances compensatory activation in homologous regions. These could normalize overactive language specific cortical regions. Furthermore, using rTMS to attenuate activation of dysfunctionally overactive prosodic or language perception areas may lead to a therapeutic effect in patients. The differential contralateral findings demonstrate the usefulness of employing cognitive or perceptual tests combined with fMRI in order to ascertain the functional effects of rTMS, and suggest the possibility that given the linguistic organi-

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