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Cerebellar involvement in verb generation: An fMRI study
Neuroscience Letters 409 (2006) 19–23
Cerebellar involvement in verb generation: An fMRI study Markus Frings a,∗ , Albena Dimitrova a , Christoph F. Schorn a , Hans-Gerd Elles a , Christoph Hein-Kropp a , Elke R. Gizewski b , Hans Christoph Diener a , Dagmar Timmann a b
a Department of Neurology, University of Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany Department of Diagnostic and Interventional Radiology and Neuroradiology, University of Essen, Hufelandstraße 55, 45122 Essen, Germany
Received 19 April 2006; received in revised form 28 July 2006; accepted 19 August 2006
Abstract A possible role of the human cerebellum in the generation of verbs corresponding to presented nouns has been suggested. Previous functional brain imaging studies have compared generation of verbs with the reading of nouns as a measure of verb generation. In the present fMRI study involving healthy human subjects, the effects of speech articulation and motor imagery associated with verb production were investigated in greater detail. Generation of verbs to visually presented nouns was compared to a condition in which subjects read those same verbs that had been individually generated by each subject. Activation in lobule HVI/Crus I of the right cerebellar hemisphere was found as a measure of verb generation. In contrast, reading of verbs as a measure of speech articulation evoked cerebellar activations in both left and right paravermal lobule VI. These results suggest an involvement of the right lateral cerebellar hemisphere in linguistic functions during verb generation. Alternatively, effects of inner speech could also possibly explain the results. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Cerebellum; Cognition; Functional magnetic resonance tomography; Inner speech; Linguistic function; Verb generation
Traditionally, it is believed that the primary function of the cerebellum is to coordinate movement [9]. During the past three decades, it has been proposed that the cerebellum may also contribute to cognition [12,19]. For example, it has been suggested that the right posterolateral cerebellum may be involved in linguistic functions [19]. Especially, a possible role of the cerebellum in verb generation has been found in some previous lesion and functional imaging studies [4,5,8,14]; however, other lesion studies were unable to show similar results [16,17]. In these previous studies, subjects were required to generate appropriate verbs in response to written nouns. In a PET study performed by Petersen et al. [14] an activation in the right lateral cerebellum was found when generation of verbs was compared with reading of nouns [14]. In this study, linguistic functions could not completely be distinguished from motor aspects of verb generation. Articulatory differences in speech associated with reading nouns and speaking generated verbs must be taken into account [6]. Furthermore, previous studies suggest that cerebellar patients are impaired in motor imagery [7,10]. Verbs may be associated with the imagination of movement. Therefore, effects of motor
∗
Corresponding author. Tel.: +49 201 723 2461; fax: +49 201 723 5901. E-mail address: [email protected] (M. Frings).
0304-3940/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2006.08.058
imagery may contribute to the results found by Petersen et al. [14]. In the present fMRI study, generation of verbs has been compared with reading of verbs in both overt and inner speech to exclude the effects of speech articulation and motor imagery. The present study was performed in 16 healthy subjects (eight male, eight female, mean age 24.9, S.D. 6.2, range 18–35 years). Subjects did not have any hearing or visual loss, had no neurological deficits, and were not taking any medication. Handedness was assessed according to the Edinburgh Handedness Inventory which ranges from −20 (completely left-handed) to +20 (completely right-handed) [13]. Mean handedness score of participants was 18.2 (S.D. 2.8), ranging from 12 to 20. All subjects gave their written informed consent. The local ethics committee approved the study. Subjects were lying on the MR-table in a supine position with their eyes opened for the duration of the experiment. By using a head coil-mounted mirror, subjects could see the words which were projected onto a screen in front of them. There were six conditions. In the verb reading conditions and in the noun reading conditions, subjects were asked to read the words on the screen. In the verb generation conditions, they were instructed to produce a verb corresponding to a noun presented on the screen (e.g., “drive” for “car”). Each of these conditions was conducted in two ways: firstly, with the instruction to read and generate the
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M. Frings et al. / Neuroscience Letters 409 (2006) 19–23
words clearly and distinctly (overt speech) and secondly, with the instruction to read and generate the words in the subjects’ own mind without moving either their lips or their tongue (inner speech). Moving of lips during the inner speech conditions was monitored by a self-constructed camera system using a fibre optic cable. In the verb generation and noun reading conditions the same 15 nouns were presented in a pseudorandom order (Trommel [drum], Schuhe [shoes], Bett [bed], Brille [glasses], Puppe [doll], Besen [broom], Fahrrad [bicycle], Handy [mobile phone], Eis [ice-cream], Kochtopf [cooking pot], Taschenlampe [pocket lamp], Fußball [football], Auto [car], Schere [scissors], Rucksack [backpack]). The verbs generated by each subject during the overt verb generation condition were recorded using a selfconstructed microphone. During the verb reading conditions, the individually generated verbs were presented to each subject. This way, verbs in the verb generation and reading conditions were the same for each individual subject. Therefore, the overt verb generation task had to be performed prior the first verb reading condition. Beyond this limitation, conditions were presented in a pseudorandom order which varied between subjects. Each condition consisted of four word blocks of 15 words each and of four rest blocks. The same words were presented in each word block, but the sequence of words varied in a pseudorandom order. The words were presented for 2 s without a pause between them. Active as well as rest blocks lasted 30 s. Between each condition and during rest blocks, the screen was white and a black fixation cross was visible in the middle of the screen, where the subjects were instructed to look at. Subjects were given detailed instructions at the beginning of the experiment. There was a training block of five trials for each condition presenting words other than those used in the actual experiment. An fMRI block-design was used. All fMRI scans were taken with a 1.5 T Siemens Sonata scanner with a standard head coil. A multislice echo planar imaging sequence (EPI) was applied to produce 33 continuous 4 mm thick axial slices covering the volume of the whole brain with repetition time (TR) = 3 s, echo time (TE) = 60 ms, flip angle = 90◦ , 64 × 64 matrix and voxel size = 3.59 mm × 3.59 mm × 3.8 mm. An electronic triggering signal was used to achieve synchronisation between the time of initiation of the active event (presentation of a word on the screen) and the MR acquisition. The stereotaxic transformations and statistical analyses ware carried out with statistical parametric mapping software (Wellcome Department of Cognitive Neurology, London, UK), version SPM2, implemented in MATLAB (Mathworks, Sherborn, MA). All individual volumes were realigned after the six head-movement parameters (three translations and three rotations) were estimated from rigid body transformations. Images were then spatially normalized into the reference system of Talairach and Tournoux [20], using a representative standard EPI template from the Montreal Neurological Institute (MNI). The functional images were subsampled to a voxel size of 2 mm × 2 mm × 2 mm and smoothed using an isotropic Gaussian kernel of 6 mm. Data from three subjects were excluded from statistical analysis because of movement artefacts.
Condition-specific effects were estimated in SPM2 with the general linear model using a boxcar approach convolved with the hemodynamic response function. The six head movement parameters were included as trial specific covariates in the design matrix. The significance of effects was assessed using Z statistics for each voxel from the brain. These sets of Z values (weighted with a linear contrast vector) were used to create statistical parametric maps (SPMs). A high-pass filter was used to remove low-frequency drifts and fluctuations in the signal, and serial autocorrelation was taken into account by means of an AR(1) correction. Group effects were calculated using random effects model analysis. Specified contrasts between cue-related activity and fixation baseline were used to identify changes in activation related to inner speech and overt speech. The overt and inner speech blocks of each verb reading, noun reading and verb generation condition were compared to identify changes in activation related to speech articulation. Verb generation blocks were compared with verb reading blocks as a measure of verb generation. In keeping with Petersen et al. [14], a comparison between verb generation blocks and noun reading blocks was also performed [14]. A threshold of P < 0.001 (uncorrected; extended threshold 20 voxels) was adopted. To cover all cerebellar activations, a small volume correction was applied to both cerebellar hemispheres, centered on the coordinates x = 26 mm and x = −26 mm, y = −60 mm, z = −34 mm with a radius of 20 mm. Cerebellar activations were attributed to an anatomical site according to the three-dimensional (3D)-atlas of the cerebellum of Schmahmann et al. [18] and to the MRI atlas of the human cerebellar nuclei of Dimitrova et al. [3], non-cerebellar activations were attributed according to the atlas of Talairach and Tournoux [20] after images were transformed from the anatomical space, as defined by the MNI template brain using the algorithms described in http://www.mrc-cbu.cam.ac.uk/Imaging/ mnispace.html [3,18,20]. Structural images were acquired for each subject using a 3D T1-weighted sequence (magnetization prepared rapid acquisition gradient-echo) with TR = 2.4 s, TE = 4.38 ms, field of view = 256 mm, slices = 160 and voxel size = 1 mm × 1 mm × 1 mm. In the word reading conditions in overt speech no errors were made. In the verb generation condition all subjects gave appropriate answers. In two subjects, the first block of the first inner speech condition was stopped after a few words and was subsequently repeated because overt speech was observed. A comparison of cue-related activity and rest blocks showed that inner speech (activation specific to inner speech, Table 1) during noun reading and during verb generation led to a blood oxygen level-dependent (BOLD) signal change in lobule HVI of the right cerebellar hemisphere, but inner speech during verb reading revealed no cerebellar activations relative to the rest blocks (P < 0.001, uncorrected, n = 13; after correction for multiple comparisons activations showed statistical significance (P < 0.05) over anatomically defined volumes of interest. Noncerebellar activations (uncorrected, P < 0.001) were found in the left and right sensorimotor and visual cortex for all inner speech conditions.
M. Frings et al. / Neuroscience Letters 409 (2006) 19–23
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Table 1 Displayed is the activity maximum of each cerebellar area with relative BOLD signal increase and corresponding T-values Activation specific to
Analysis
Inner speech
Verb reading Noun reading Verb generation
Inner speech
Verb reading
Overt speech
Overt speech
Noun reading Verb generation Articulation
Verb reading
Overt vs. inner speech
Noun reading Verb generation Verb generation
Verb generation vs. verb reading Verb generation vs. noun reading
Inner speech Overt speech Overt and inner speech Inner speech Overt speech Overt and inner speech
x, y, z (mm)
T-value
Area
28, −60, −30 32, −72, −24
6.93 10.72
No cerebellar activation Right lobule HVI Right lobule HVI
−20, −62, −20 18, −66, −18 −26, −64, −20 24, −58, −26 −24, −64, −22 18, −62, −22
6.57 7.94 9.42 10.81 8.25 7.65
Left paravermal lobule VI Right paravermal lobule VI Left paravermal lobule VI Right paravermal lobule VI Left paravermal lobule VI Right paravermal lobule VI
−18, −62, −16 18, −64, −20 −18, −60, −20 22, −60, −26 −20, −64, −22 16, −60, −22
10.55 7.01 7.40 8.15 6.75 8.63
Left paravermal lobule VI Right paravermal lobule VI Left paravermal lobule VI Right paravermal lobule VI Left paravermal lobule VI Right paravermal lobule VI
48, −60, −30 30, −56, −34
12.36 6.05
30, −58, −30
6.66
Right Crus I Right lobule HVI No cerebellar activation Right lobule HVI No cerebellar activation No cerebellar activation No cerebellar activation
Anatomical identification was performed according to the atlas of Schmahmann et al. [18]. P < 0.001, uncorrected, n = 13; after correction for multiple comparisons all activations showed statistical significance (P < 0.05) over anatomically defined volumes of interest.
A comparison of overt and inner speech during verb reading (Fig. 1A), noun reading and during verb generation conditions (activation specific to articulation) revealed relative activation increases in left and right paravermal lobule VI. Non-cerebellar activations (uncorrected, P < 0.001) were found in the left and right sensorimotor cortex.
Comparison of verb generation and verb reading (activation specific to verb generation) in inner speech, but not in overt speech led to an activation in lobule HVI/Crus I of the right cerebellar hemisphere (Fig. 1B). Non-cerebellar activations (uncorrected, P < 0.001) were found in the left superior temporal and left inferior frontal gyrus. Taking inner and overt
Fig. 1. SPM{t} map of fMRI data (P < 0.001, uncorrected, n = 13; after correction for multiple comparisons all activations showed statistical significance (P < 0.05) over anatomically defined volumes of interest) superimposed on an MRI template adapted to a standard brain. (A) Comparison of the conditions “verb reading in overt speech” and “verb reading in inner speech” as a measure of speech articulation. Cerebellar activations were found in left and right paravermal lobule VI (x = −18 mm, y = −62 mm, z = −16 mm, T-value 10.55 and x = 18 mm, y = −64 mm, z = −20 mm, T-value 7.01). (B) Comparison of the conditions “verb generation in inner speech” and “verb reading in inner speech” as a measure of verb generation. Cerebellar activations were found in lobule HVI and Crus I of the right cerebellar hemisphere (x = 30 mm, y = −56 mm, z = −34 mm, T-value 6.05 and x = 48 mm, y = −60 mm, z = −30mm, T-value 12.36).
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M. Frings et al. / Neuroscience Letters 409 (2006) 19–23
Table 2 Three cerebellar areas with an activation specific to verb generation from Table 1 are presented with corresponding effect sizes (contrast of parameter estimates with a 90% confidence interval) separately for the six different conditions Coordinates (x, y, z (mm)) Area
48 −60 −30 Right Crus I
Verb reading in inner speech Noun reading in inner speech Verb generation in inner speech Verb reading in overt speech Noun reading in overt speech Verb generation in overt speech
0.02 0.49 0.82 0.75 0.60 1.20
± ± ± ± ± ±
0.31 0.18 0.30 0.37 0.26 0.62
speech together, a comparison of verb generation and verb reading revealed an activation in the right lobule HVI. A comparison of verb generation and noun reading did not reveal cerebellar activations during inner speech, overt speech, or when both inner and overt speech were taken together. The effect sizes (contrast parameter estimates with a 90% confidence interval) for the activity maxima of the three cerebellar areas with an activation specific to verb generation are presented in Table 2. In the present study, the results show that verb generation was associated with an activation in lobule HVI/Crus I of the right cerebellar hemisphere. In addition, bilateral activations in paravermal cerebellar lobules VI were found in association with speech articulation. The paravermal activations related to speech articulation were a consistent finding in three different conditions comparing overt and inner speech. These results confirm previous brain imaging studies which suggested a role of the superior paravermal cerebellum in motor speech control [21]. These results are also consistent with a human lesion study which investigated the cerebellar regions critical for the development of ataxic dysarthria [11]. In the previous study by Petersen et al. [14], verb generation and noun reading conditions have been compared [14]. In the present study, comparisons were made between verb generation and verb reading. Motor effects of articulatory differences between verbs and nouns and of motor imagery associated with speaking of verbs have been excluded [6,7,10]. As a measure of verb generation an activation in lobule HVI/Crus I of the right cerebellar hemisphere was found lateral from the paravermal activation of lobule VI associated with speech articulation. The activation of lobule HVI/Crus I might reflect a linguistic function in verb generation, e.g., in semantic search. However, impairments in verb generation have not been shown in every study involving patients with cerebellar lesions. For example, Richter and co-workers found effects of dysarthria only [16,17]. The activation in right lobule HVI was not only found as a measure of verb generation but also as a measure of noun reading in inner speech. This is an argument against an involvement of this area in linguistic functions. Ackermann et al. [2] showed in an fMRI study that an activation within the same region of lobule HVI/Crus I was found during silent recitation (inner speech) of the names of the months of the year. An involvement of the lateral cerebellum in the timing aspects of both inner and overt speech production rather than in cognitive operations has been proposed. In contrast to the verb reading condition, the verb generation condition requires lexical search processes.
30 −56 −34 Right lobule HVI
30 −58 −30 Right lobule HVI
−0.11 0.48 0.53 0.12 0.09 0.47
−0.08 0.55 0.74 0.15 0.82 0.69
± ± ± ± ± ±
0.20 0.21 0.24 0.25 0.31 0.38
± ± ± ± ± ±
0.20 0.50 0.26 0.18 0.42 0.20
These search processes likely involve subvocal representations (“inner speech”) [1]. Therefore, lobule HVI may be involved in inner speech during reading and in “inner speech” during lexical search processes of verb generation. The differences in the changes of BOLD effects during the verb generation and reading tasks might reflect different contributions of inner speech. However, in the present study cerebellar activations could be found only during inner speech of noun reading, but not during inner speech of verb reading. This is in contrast to the study by Ackermann et al. [2]. However, in that study, the authors used highly overlearned word strings (“automatic speech”) generated by silent recitation of the names of the months of the year, which demanded mostly articulatory aspects of speech production [2]. In the present study the tempo of inner speech was considerably slower with one word in two seconds. Therefore, the lack of cerebellar activations during inner speech in the present verb reading condition may reflect a possible threshold effect. Comparison of verb generation with verb reading in overt speech did not reveal an activation in the right cerebellar hemisphere in contrast to inner speech. Analysis of effect sizes suggests that the lack of activation resulted from a higher effect size for verb reading in overt speech (see Table 2). On the other hand, verb generation in overt as well as in inner speech was associated with higher effect sizes than the reading conditions. Given that reading involves more than speech articulation, it cannot be decided if the higher verbgeneration-related activation in right lobule HVI was due to higher demands in inner speech or in linguistic function. In contrast to the study by Petersen et al. [14], no cerebellar activations were found comparing verb generation with reading of nouns [14]. A previous PET study revealed practice-related decreases of regional cerebral blood flow in the right cerebellar hemisphere during verb generation [15]. In other words, brief practice made verb generation indistinguishable from repetition of words. In the present study, practice-related decreases of cerebellar activity cannot be excluded because both vocal and inner speech conditions of verb generation had to be performed. Order effects could also possibly explain the lack of cerebellar activations when comparing verb generation with noun reading. The order of noun reading and verb generation was randomized. However, the condition of overt verb generation had to be performed before the overt and inner speech conditions of verb reading. Higher efforts in executive/articulatory planning during earlier sessions which later habituate may have contributed to cerebellar activation when verb generation was compared with
M. Frings et al. / Neuroscience Letters 409 (2006) 19–23
verb reading, but not when verb generation was compared with noun reading. In the present study, two distinct cerebellar areas within lobule VI were found to be involved in speech production and verb generation. Speech production relied on paravermal lobule VI bilaterally, whereas verb generation was associated with a lateral hemispheral part of lobule VI. Verb generation-related cerebellar activation may be explained by linguistic functions of the cerebellum or by its involvement in inner speech. Acknowledgments The study was supported by grant from the Deutsche Forschungsgemeinschaft (DFG Ti 239/5-2). We thank D.B. Debicki, Department of Physiology and Pharmacology, University of Western Ontario, for revising the text as native English speaker. References [1] H. Ackermann, K. Mathiak, R.B. Ivry, Temporal organization of “internal speech” as a basis for cerebellar modulation of cognitive functions, Behav. Cogn. Neurosci. Rev. 3 (2004) 14–22. [2] H. Ackermann, D. Wildgruber, I. Daum, W. Grodd, Does the cerebellum contribute to cognitive aspects of speech production? A functional magnetic resonance imaging (fMRI) study in humans, Neurosci. Lett. 247 (1998) 187–190. [3] A. Dimitrova, D. Zeljko, F. Schwarze, M. Maschke, M. Gerwig, M. Frings, A. Beck, V. Aurich, M. Forsting, D. Timmann, Probabilistic 3D MRI atlas of the human dentate/interposed nuclei, Neuroimage 30 (2006) 12–25. [4] J.A. Fiez, S.E. Petersen, M.K. Cheney, M.E. Raichle, Impaired non-motor learning and error detection associated with cerebellar damage. A single case study, Brain 115 (1992) 155–178. [5] A. Gebhart, S. Petersen, W.T. Thach, Evidence for functional lateralization of language operations to the right posterior cerebellum, Soc. Neurosci. Abstr. 26 (2000) 1246. [6] D. Genter, Some interesting differences between verbs and nouns, Cogn. Brain Theory 42 (1981) 161–178.
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[7] B. Gonzalez, M. Rodriguez, C. Ramirez, M. Sabate, Disturbance of motor imagery after cerebellar stroke, Behav. Neurosci. 119 (2005) 622– 626. [8] L.L. Helmuth, R.B. Ivry, N. Shimizu, Preserved performance by cerebellar patients on tests of word generation, discrimination learning, and attention, Learn. Mem. 3 (1997) 456–474. [9] G. Holmes, The cerebellum of man, Brain 62 (1939) 1–30. [10] F.A. Kagerer, V. Bracha, D.A. Wunderlich, G.E. Stelmach, J.R. Bloedel, Ataxia reflected in the simulated movements of patients with cerebellar lesions, Exp. Brain Res. 121 (1989) 125–134. [11] R. Lechtenberg, S. Gilman, Speech disorders in cerebellar disease, Ann. Neurol. 3 (1978) 285–290. [12] H.C. Leiner, A.L. Leiner, R.S. Dow, Does the cerebellum contribute to mental skills? Behav. Neurosci. 100 (1986) 443–454. [13] R.C. OIdfield, The assessment and analysis of handedness: the Edinburgh inventory, Neuropsychologia 9 (1979) 97–113. [14] S.E. Petersen, P.T. Fox, M.L. Posner, M. Mintun, M.E. Raichle, Positron emission tomographic studies of the processing of single words, J. Cognit. Neurosci. 1 (1989) 153–170. [15] M.E. Raichle, J.A. Fiez, T.O. Videen, A.M. MacLeod, J.V. Pardo, P.T. Fox, S.E. Petersen, Practice-related changes in human brain functional anatomy during nonmotor learning, Cereb. Cortex 4 (1994) 8–26. [16] S. Richter, O. Kaiser, C. Hein-Kropp, A. Dimitrova, E. Gizewski, A. Beck, V. Aurich, W. Ziegler, D. Timmann, Preserved verb generation in patients with cerebellar atrophy, Neuropsychologia 42 (2004) 1235– 1246. [17] S. Richter, B. Schoch, O. Kaiser, H. Groetschel, C. Hein-Kropp, M. Maschke, A. Dimitrova, E. Gizewski, W. Ziegler, H.O. Karnath, D. Timmann, Children and adolescents with chronic cerebellar lesions show no clinically relevant signs of aphasia or neglect, J. Neurophysiol. 94 (2005) 4108–4120. [18] J.D. Schmahmann, J. Doyon, A.W. Toga, M. Petrides, A.C. Evans, MRI Atlas of the Human Cerebellum, Academic Press, San Diego, 2000. [19] J.D. Schmahmann, Disorders of the cerebellum: Ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome, J. Neuropsych. Clin. Neurosci. 16 (2004) 367–378. [20] J. Talairach, P. Tournoux, Co-planar Stereotaxis Atlas of the Human Brain, Georg-Thieme, New York, 1988. [21] D. Wildgruber, H. Ackermann, W. Grodd, Differential contributions of motor cortex, basal ganglia, and cerebellum to speech motor control: Effects of syllable repetition rate evaluated by fMRI, Neuroimage 13 (2001) 101–109.
Cerebellar involvement in verb generation: An fMRI study Markus Frings a,∗ , Albena Dimitrova a , Christoph F. Schorn a , Hans-Gerd Elles a , Christoph Hein-Kropp a , Elke R. Gizewski b , Hans Christoph Diener a , Dagmar Timmann a b
a Department of Neurology, University of Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany Department of Diagnostic and Interventional Radiology and Neuroradiology, University of Essen, Hufelandstraße 55, 45122 Essen, Germany
Received 19 April 2006; received in revised form 28 July 2006; accepted 19 August 2006
Abstract A possible role of the human cerebellum in the generation of verbs corresponding to presented nouns has been suggested. Previous functional brain imaging studies have compared generation of verbs with the reading of nouns as a measure of verb generation. In the present fMRI study involving healthy human subjects, the effects of speech articulation and motor imagery associated with verb production were investigated in greater detail. Generation of verbs to visually presented nouns was compared to a condition in which subjects read those same verbs that had been individually generated by each subject. Activation in lobule HVI/Crus I of the right cerebellar hemisphere was found as a measure of verb generation. In contrast, reading of verbs as a measure of speech articulation evoked cerebellar activations in both left and right paravermal lobule VI. These results suggest an involvement of the right lateral cerebellar hemisphere in linguistic functions during verb generation. Alternatively, effects of inner speech could also possibly explain the results. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Cerebellum; Cognition; Functional magnetic resonance tomography; Inner speech; Linguistic function; Verb generation
Traditionally, it is believed that the primary function of the cerebellum is to coordinate movement [9]. During the past three decades, it has been proposed that the cerebellum may also contribute to cognition [12,19]. For example, it has been suggested that the right posterolateral cerebellum may be involved in linguistic functions [19]. Especially, a possible role of the cerebellum in verb generation has been found in some previous lesion and functional imaging studies [4,5,8,14]; however, other lesion studies were unable to show similar results [16,17]. In these previous studies, subjects were required to generate appropriate verbs in response to written nouns. In a PET study performed by Petersen et al. [14] an activation in the right lateral cerebellum was found when generation of verbs was compared with reading of nouns [14]. In this study, linguistic functions could not completely be distinguished from motor aspects of verb generation. Articulatory differences in speech associated with reading nouns and speaking generated verbs must be taken into account [6]. Furthermore, previous studies suggest that cerebellar patients are impaired in motor imagery [7,10]. Verbs may be associated with the imagination of movement. Therefore, effects of motor
∗
Corresponding author. Tel.: +49 201 723 2461; fax: +49 201 723 5901. E-mail address: [email protected] (M. Frings).
0304-3940/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2006.08.058
imagery may contribute to the results found by Petersen et al. [14]. In the present fMRI study, generation of verbs has been compared with reading of verbs in both overt and inner speech to exclude the effects of speech articulation and motor imagery. The present study was performed in 16 healthy subjects (eight male, eight female, mean age 24.9, S.D. 6.2, range 18–35 years). Subjects did not have any hearing or visual loss, had no neurological deficits, and were not taking any medication. Handedness was assessed according to the Edinburgh Handedness Inventory which ranges from −20 (completely left-handed) to +20 (completely right-handed) [13]. Mean handedness score of participants was 18.2 (S.D. 2.8), ranging from 12 to 20. All subjects gave their written informed consent. The local ethics committee approved the study. Subjects were lying on the MR-table in a supine position with their eyes opened for the duration of the experiment. By using a head coil-mounted mirror, subjects could see the words which were projected onto a screen in front of them. There were six conditions. In the verb reading conditions and in the noun reading conditions, subjects were asked to read the words on the screen. In the verb generation conditions, they were instructed to produce a verb corresponding to a noun presented on the screen (e.g., “drive” for “car”). Each of these conditions was conducted in two ways: firstly, with the instruction to read and generate the
20
M. Frings et al. / Neuroscience Letters 409 (2006) 19–23
words clearly and distinctly (overt speech) and secondly, with the instruction to read and generate the words in the subjects’ own mind without moving either their lips or their tongue (inner speech). Moving of lips during the inner speech conditions was monitored by a self-constructed camera system using a fibre optic cable. In the verb generation and noun reading conditions the same 15 nouns were presented in a pseudorandom order (Trommel [drum], Schuhe [shoes], Bett [bed], Brille [glasses], Puppe [doll], Besen [broom], Fahrrad [bicycle], Handy [mobile phone], Eis [ice-cream], Kochtopf [cooking pot], Taschenlampe [pocket lamp], Fußball [football], Auto [car], Schere [scissors], Rucksack [backpack]). The verbs generated by each subject during the overt verb generation condition were recorded using a selfconstructed microphone. During the verb reading conditions, the individually generated verbs were presented to each subject. This way, verbs in the verb generation and reading conditions were the same for each individual subject. Therefore, the overt verb generation task had to be performed prior the first verb reading condition. Beyond this limitation, conditions were presented in a pseudorandom order which varied between subjects. Each condition consisted of four word blocks of 15 words each and of four rest blocks. The same words were presented in each word block, but the sequence of words varied in a pseudorandom order. The words were presented for 2 s without a pause between them. Active as well as rest blocks lasted 30 s. Between each condition and during rest blocks, the screen was white and a black fixation cross was visible in the middle of the screen, where the subjects were instructed to look at. Subjects were given detailed instructions at the beginning of the experiment. There was a training block of five trials for each condition presenting words other than those used in the actual experiment. An fMRI block-design was used. All fMRI scans were taken with a 1.5 T Siemens Sonata scanner with a standard head coil. A multislice echo planar imaging sequence (EPI) was applied to produce 33 continuous 4 mm thick axial slices covering the volume of the whole brain with repetition time (TR) = 3 s, echo time (TE) = 60 ms, flip angle = 90◦ , 64 × 64 matrix and voxel size = 3.59 mm × 3.59 mm × 3.8 mm. An electronic triggering signal was used to achieve synchronisation between the time of initiation of the active event (presentation of a word on the screen) and the MR acquisition. The stereotaxic transformations and statistical analyses ware carried out with statistical parametric mapping software (Wellcome Department of Cognitive Neurology, London, UK), version SPM2, implemented in MATLAB (Mathworks, Sherborn, MA). All individual volumes were realigned after the six head-movement parameters (three translations and three rotations) were estimated from rigid body transformations. Images were then spatially normalized into the reference system of Talairach and Tournoux [20], using a representative standard EPI template from the Montreal Neurological Institute (MNI). The functional images were subsampled to a voxel size of 2 mm × 2 mm × 2 mm and smoothed using an isotropic Gaussian kernel of 6 mm. Data from three subjects were excluded from statistical analysis because of movement artefacts.
Condition-specific effects were estimated in SPM2 with the general linear model using a boxcar approach convolved with the hemodynamic response function. The six head movement parameters were included as trial specific covariates in the design matrix. The significance of effects was assessed using Z statistics for each voxel from the brain. These sets of Z values (weighted with a linear contrast vector) were used to create statistical parametric maps (SPMs). A high-pass filter was used to remove low-frequency drifts and fluctuations in the signal, and serial autocorrelation was taken into account by means of an AR(1) correction. Group effects were calculated using random effects model analysis. Specified contrasts between cue-related activity and fixation baseline were used to identify changes in activation related to inner speech and overt speech. The overt and inner speech blocks of each verb reading, noun reading and verb generation condition were compared to identify changes in activation related to speech articulation. Verb generation blocks were compared with verb reading blocks as a measure of verb generation. In keeping with Petersen et al. [14], a comparison between verb generation blocks and noun reading blocks was also performed [14]. A threshold of P < 0.001 (uncorrected; extended threshold 20 voxels) was adopted. To cover all cerebellar activations, a small volume correction was applied to both cerebellar hemispheres, centered on the coordinates x = 26 mm and x = −26 mm, y = −60 mm, z = −34 mm with a radius of 20 mm. Cerebellar activations were attributed to an anatomical site according to the three-dimensional (3D)-atlas of the cerebellum of Schmahmann et al. [18] and to the MRI atlas of the human cerebellar nuclei of Dimitrova et al. [3], non-cerebellar activations were attributed according to the atlas of Talairach and Tournoux [20] after images were transformed from the anatomical space, as defined by the MNI template brain using the algorithms described in http://www.mrc-cbu.cam.ac.uk/Imaging/ mnispace.html [3,18,20]. Structural images were acquired for each subject using a 3D T1-weighted sequence (magnetization prepared rapid acquisition gradient-echo) with TR = 2.4 s, TE = 4.38 ms, field of view = 256 mm, slices = 160 and voxel size = 1 mm × 1 mm × 1 mm. In the word reading conditions in overt speech no errors were made. In the verb generation condition all subjects gave appropriate answers. In two subjects, the first block of the first inner speech condition was stopped after a few words and was subsequently repeated because overt speech was observed. A comparison of cue-related activity and rest blocks showed that inner speech (activation specific to inner speech, Table 1) during noun reading and during verb generation led to a blood oxygen level-dependent (BOLD) signal change in lobule HVI of the right cerebellar hemisphere, but inner speech during verb reading revealed no cerebellar activations relative to the rest blocks (P < 0.001, uncorrected, n = 13; after correction for multiple comparisons activations showed statistical significance (P < 0.05) over anatomically defined volumes of interest. Noncerebellar activations (uncorrected, P < 0.001) were found in the left and right sensorimotor and visual cortex for all inner speech conditions.
M. Frings et al. / Neuroscience Letters 409 (2006) 19–23
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Table 1 Displayed is the activity maximum of each cerebellar area with relative BOLD signal increase and corresponding T-values Activation specific to
Analysis
Inner speech
Verb reading Noun reading Verb generation
Inner speech
Verb reading
Overt speech
Overt speech
Noun reading Verb generation Articulation
Verb reading
Overt vs. inner speech
Noun reading Verb generation Verb generation
Verb generation vs. verb reading Verb generation vs. noun reading
Inner speech Overt speech Overt and inner speech Inner speech Overt speech Overt and inner speech
x, y, z (mm)
T-value
Area
28, −60, −30 32, −72, −24
6.93 10.72
No cerebellar activation Right lobule HVI Right lobule HVI
−20, −62, −20 18, −66, −18 −26, −64, −20 24, −58, −26 −24, −64, −22 18, −62, −22
6.57 7.94 9.42 10.81 8.25 7.65
Left paravermal lobule VI Right paravermal lobule VI Left paravermal lobule VI Right paravermal lobule VI Left paravermal lobule VI Right paravermal lobule VI
−18, −62, −16 18, −64, −20 −18, −60, −20 22, −60, −26 −20, −64, −22 16, −60, −22
10.55 7.01 7.40 8.15 6.75 8.63
Left paravermal lobule VI Right paravermal lobule VI Left paravermal lobule VI Right paravermal lobule VI Left paravermal lobule VI Right paravermal lobule VI
48, −60, −30 30, −56, −34
12.36 6.05
30, −58, −30
6.66
Right Crus I Right lobule HVI No cerebellar activation Right lobule HVI No cerebellar activation No cerebellar activation No cerebellar activation
Anatomical identification was performed according to the atlas of Schmahmann et al. [18]. P < 0.001, uncorrected, n = 13; after correction for multiple comparisons all activations showed statistical significance (P < 0.05) over anatomically defined volumes of interest.
A comparison of overt and inner speech during verb reading (Fig. 1A), noun reading and during verb generation conditions (activation specific to articulation) revealed relative activation increases in left and right paravermal lobule VI. Non-cerebellar activations (uncorrected, P < 0.001) were found in the left and right sensorimotor cortex.
Comparison of verb generation and verb reading (activation specific to verb generation) in inner speech, but not in overt speech led to an activation in lobule HVI/Crus I of the right cerebellar hemisphere (Fig. 1B). Non-cerebellar activations (uncorrected, P < 0.001) were found in the left superior temporal and left inferior frontal gyrus. Taking inner and overt
Fig. 1. SPM{t} map of fMRI data (P < 0.001, uncorrected, n = 13; after correction for multiple comparisons all activations showed statistical significance (P < 0.05) over anatomically defined volumes of interest) superimposed on an MRI template adapted to a standard brain. (A) Comparison of the conditions “verb reading in overt speech” and “verb reading in inner speech” as a measure of speech articulation. Cerebellar activations were found in left and right paravermal lobule VI (x = −18 mm, y = −62 mm, z = −16 mm, T-value 10.55 and x = 18 mm, y = −64 mm, z = −20 mm, T-value 7.01). (B) Comparison of the conditions “verb generation in inner speech” and “verb reading in inner speech” as a measure of verb generation. Cerebellar activations were found in lobule HVI and Crus I of the right cerebellar hemisphere (x = 30 mm, y = −56 mm, z = −34 mm, T-value 6.05 and x = 48 mm, y = −60 mm, z = −30mm, T-value 12.36).
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M. Frings et al. / Neuroscience Letters 409 (2006) 19–23
Table 2 Three cerebellar areas with an activation specific to verb generation from Table 1 are presented with corresponding effect sizes (contrast of parameter estimates with a 90% confidence interval) separately for the six different conditions Coordinates (x, y, z (mm)) Area
48 −60 −30 Right Crus I
Verb reading in inner speech Noun reading in inner speech Verb generation in inner speech Verb reading in overt speech Noun reading in overt speech Verb generation in overt speech
0.02 0.49 0.82 0.75 0.60 1.20
± ± ± ± ± ±
0.31 0.18 0.30 0.37 0.26 0.62
speech together, a comparison of verb generation and verb reading revealed an activation in the right lobule HVI. A comparison of verb generation and noun reading did not reveal cerebellar activations during inner speech, overt speech, or when both inner and overt speech were taken together. The effect sizes (contrast parameter estimates with a 90% confidence interval) for the activity maxima of the three cerebellar areas with an activation specific to verb generation are presented in Table 2. In the present study, the results show that verb generation was associated with an activation in lobule HVI/Crus I of the right cerebellar hemisphere. In addition, bilateral activations in paravermal cerebellar lobules VI were found in association with speech articulation. The paravermal activations related to speech articulation were a consistent finding in three different conditions comparing overt and inner speech. These results confirm previous brain imaging studies which suggested a role of the superior paravermal cerebellum in motor speech control [21]. These results are also consistent with a human lesion study which investigated the cerebellar regions critical for the development of ataxic dysarthria [11]. In the previous study by Petersen et al. [14], verb generation and noun reading conditions have been compared [14]. In the present study, comparisons were made between verb generation and verb reading. Motor effects of articulatory differences between verbs and nouns and of motor imagery associated with speaking of verbs have been excluded [6,7,10]. As a measure of verb generation an activation in lobule HVI/Crus I of the right cerebellar hemisphere was found lateral from the paravermal activation of lobule VI associated with speech articulation. The activation of lobule HVI/Crus I might reflect a linguistic function in verb generation, e.g., in semantic search. However, impairments in verb generation have not been shown in every study involving patients with cerebellar lesions. For example, Richter and co-workers found effects of dysarthria only [16,17]. The activation in right lobule HVI was not only found as a measure of verb generation but also as a measure of noun reading in inner speech. This is an argument against an involvement of this area in linguistic functions. Ackermann et al. [2] showed in an fMRI study that an activation within the same region of lobule HVI/Crus I was found during silent recitation (inner speech) of the names of the months of the year. An involvement of the lateral cerebellum in the timing aspects of both inner and overt speech production rather than in cognitive operations has been proposed. In contrast to the verb reading condition, the verb generation condition requires lexical search processes.
30 −56 −34 Right lobule HVI
30 −58 −30 Right lobule HVI
−0.11 0.48 0.53 0.12 0.09 0.47
−0.08 0.55 0.74 0.15 0.82 0.69
± ± ± ± ± ±
0.20 0.21 0.24 0.25 0.31 0.38
± ± ± ± ± ±
0.20 0.50 0.26 0.18 0.42 0.20
These search processes likely involve subvocal representations (“inner speech”) [1]. Therefore, lobule HVI may be involved in inner speech during reading and in “inner speech” during lexical search processes of verb generation. The differences in the changes of BOLD effects during the verb generation and reading tasks might reflect different contributions of inner speech. However, in the present study cerebellar activations could be found only during inner speech of noun reading, but not during inner speech of verb reading. This is in contrast to the study by Ackermann et al. [2]. However, in that study, the authors used highly overlearned word strings (“automatic speech”) generated by silent recitation of the names of the months of the year, which demanded mostly articulatory aspects of speech production [2]. In the present study the tempo of inner speech was considerably slower with one word in two seconds. Therefore, the lack of cerebellar activations during inner speech in the present verb reading condition may reflect a possible threshold effect. Comparison of verb generation with verb reading in overt speech did not reveal an activation in the right cerebellar hemisphere in contrast to inner speech. Analysis of effect sizes suggests that the lack of activation resulted from a higher effect size for verb reading in overt speech (see Table 2). On the other hand, verb generation in overt as well as in inner speech was associated with higher effect sizes than the reading conditions. Given that reading involves more than speech articulation, it cannot be decided if the higher verbgeneration-related activation in right lobule HVI was due to higher demands in inner speech or in linguistic function. In contrast to the study by Petersen et al. [14], no cerebellar activations were found comparing verb generation with reading of nouns [14]. A previous PET study revealed practice-related decreases of regional cerebral blood flow in the right cerebellar hemisphere during verb generation [15]. In other words, brief practice made verb generation indistinguishable from repetition of words. In the present study, practice-related decreases of cerebellar activity cannot be excluded because both vocal and inner speech conditions of verb generation had to be performed. Order effects could also possibly explain the lack of cerebellar activations when comparing verb generation with noun reading. The order of noun reading and verb generation was randomized. However, the condition of overt verb generation had to be performed before the overt and inner speech conditions of verb reading. Higher efforts in executive/articulatory planning during earlier sessions which later habituate may have contributed to cerebellar activation when verb generation was compared with
M. Frings et al. / Neuroscience Letters 409 (2006) 19–23
verb reading, but not when verb generation was compared with noun reading. In the present study, two distinct cerebellar areas within lobule VI were found to be involved in speech production and verb generation. Speech production relied on paravermal lobule VI bilaterally, whereas verb generation was associated with a lateral hemispheral part of lobule VI. Verb generation-related cerebellar activation may be explained by linguistic functions of the cerebellum or by its involvement in inner speech. Acknowledgments The study was supported by grant from the Deutsche Forschungsgemeinschaft (DFG Ti 239/5-2). We thank D.B. Debicki, Department of Physiology and Pharmacology, University of Western Ontario, for revising the text as native English speaker. References [1] H. Ackermann, K. Mathiak, R.B. Ivry, Temporal organization of “internal speech” as a basis for cerebellar modulation of cognitive functions, Behav. Cogn. Neurosci. Rev. 3 (2004) 14–22. [2] H. Ackermann, D. Wildgruber, I. Daum, W. Grodd, Does the cerebellum contribute to cognitive aspects of speech production? A functional magnetic resonance imaging (fMRI) study in humans, Neurosci. Lett. 247 (1998) 187–190. [3] A. Dimitrova, D. Zeljko, F. Schwarze, M. Maschke, M. Gerwig, M. Frings, A. Beck, V. Aurich, M. Forsting, D. Timmann, Probabilistic 3D MRI atlas of the human dentate/interposed nuclei, Neuroimage 30 (2006) 12–25. [4] J.A. Fiez, S.E. Petersen, M.K. Cheney, M.E. Raichle, Impaired non-motor learning and error detection associated with cerebellar damage. A single case study, Brain 115 (1992) 155–178. [5] A. Gebhart, S. Petersen, W.T. Thach, Evidence for functional lateralization of language operations to the right posterior cerebellum, Soc. Neurosci. Abstr. 26 (2000) 1246. [6] D. Genter, Some interesting differences between verbs and nouns, Cogn. Brain Theory 42 (1981) 161–178.
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