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Lateralized organization of the cerebellum in a silent verbal fluency task: a functional magnetic resonance imaging study in healthy volunteers
Neuroscience Letters 319 (2002) 91–94 www.elsevier.com/locate/neulet
Lateralized organization of the cerebellum in a silent verbal fluency task: a functional magnetic resonance imaging study in healthy volunteers Petra Hubrich-Ungureanu*, Nina Kaemmerer, Fritz A. Henn, Dieter F. Braus Central Institute of Mental Health (ZI), NMR-Research, P.O. Box 122 120, D-68072, Mannheim, Germany Received 31 October 2001; received in revised form 7 December 2001; accepted 7 December 2001
Abstract Functionally, the cerebellum is not only involved in motor control but is also thought to influence higher cognitive function including language. Anatomical data would suggest crossed reciprocal connections between the cerebellum and higher order cortical association areas. In the following study, one left- and one right-handed female volunteer underwent functional magnetic resonance imaging in a conventional block design. Regions of activation were detected after performance of a silent verbal fluency task inside the scanner. In the right-handed volunteer we found an activation of the left fronto-parietal cortex and the right cerebellar hemisphere, while in the left-handed volunteer the activation was seen in the right fronto-parieto-temporal cortex and the left cerebellar hemisphere. These initial results demonstrate that cerebellar activation is contralateral to the activation of the frontal cortex even under conditions of different language dominance. They provide evidence for the hypothesis of a lateralized organization of the cerebellum crossed to the cerebral hemispheres in supporting higher cognitive function. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cerebellum; Higher cognitive function; Language; Handedness; Lateralization; Schizophrenia; Functional magnetic resonance imaging
Traditional neurologic teaching suggests that functionally the cerebellum is mainly involved in motor control, although this view has been increasingly challenged over the past decade. Phylogenetically, the neocerebellum developed and enlarged parallel to the newer cerebral association areas [8]. Strong, crossed reciprocal connections to higher order cerebral association areas have been shown, especially to the prefrontal cortex [14]. The afferent pathway is connected via the pons, the efferent pathway via the thalamus [15]. A growing body of empirical data, largely derived from functional imaging studies, shows the cerebellum’s involvement in a number of higher cognitive functions. In positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies, the participation of the cerebellum has been seen in different cognitive tasks associated with memory, language, attention, mental imagery and problem solving [1,4,6,11,13]. * Corresponding author. Tel.: 149-621-1703-205; fax: 149-6211703-673. E-mail address: [email protected] (P. Hubrich-Ungureanu).
In patients with cerebellar lesions cognitive, affective and behavioral deficits have been observed in addition to motor deficits, a cluster of symptoms now known as the cerebellar cognitive affective syndrome [16]. The cerebellum is also regarded as a node in altered circuits underlying some mental diseases. Thought disorders in schizophrenia are assumed to be a symptom of cerebellar dysfunction called ‘cognitive dysmetria’. Finally, there is a growing body of evidence suggesting that the disturbed circuit underlying schizophrenia consists of the frontal cortex, the thalamus and the cerebellum (CCTCC) [2]. The asymmetric organization of the cerebral cortex is well known. In right-handed individuals, language dominance is mostly represented in the left hemisphere, whereas in approximately 27% of strong left-handed persons the functional dominance of the hemispheres is reversed [7]. This leads to the hypothesis that there might also be a lateralized functional organization of the cerebellum, which shows a crosswise link to the hemispheres in the modulation of higher cognitive functions. To contribute to this question, the present case study used
0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 1) 02 56 6- 6
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P. Hubrich-Ungureanu et al. / Neuroscience Letters 319 (2002) 91–94
verbal fluency, a well-established paradigm for testing language function [12] in combination with fMRI [9]. We examined two healthy females, one being right- and the other left-handed. Neither had a history of drug abuse, they were mentally normal and had no family history of psychiatric illness. Prior to the fMRI examination handedness was determined with the Edinburgh handedness inventory [10]. For performance control volunteers had been asked to generate words aloud three times prior to data acquisition (S,A,B). During fMRI, verbal fluency was tested by silent performance of the task. The silent condition was chosen to reduce motor artifacts and to assure that the cerebellar activation was indeed due to verbal generation and not articulation. Volunteers were asked to generate words beginning with letters, which had previously been sounded to them over the intercom. The letters for the seven activation conditions were E, F, G, U, W, R and P. After scanning, they were then asked to give examples of the words they had generated in the silent condition and to estimate the amount of words they had generated in each category. During the resting condition volunteers simply relaxed. Written informed consent had been obtained prior to the examination and the study had been approved by the local ethics committee. Imaging was performed on a standard clinical 1.5 T MRI Scanner (Siemens Visionw). For fMRI a standard EPISequence (TE ¼ 66 ms, a ¼ 908, repetition time every 4 s) with an in plane resolution of 64 £ 64 pixels (28 slices, 4 mm thickness, gap 1 mm, FoV 220 mm) was used. For anatomical reference a 3D Magnitization Prepared Rapid Gradient Echo (MPRAGE) image data set was acquired. fMRI slices were oriented axially parallel to the AC–PC line according to
Talairach and Tournoux [19]. Each functional T2* slice was imaged 140 times over a total period of 560 s. Data analysis was performed using custom software (Brainvoyager 4.2) [5]. Prior to statistical analysis the time series of functional images was aligned for each slice in order to minimize the effects of head movement. In order to statistically evaluate the differences between stimulation conditions cross-correlation analysis was applied. For the computation of correlation maps, the stimulation protocol served as a box car reference function reflecting the temporal sequence of stimulation and control conditions [3]. For the actual study, we recruited a 33 and a 35-year-old woman, the former right- and the latter left-handed. The degree of handedness was 100 in the right-handed and 275 in the left-handed proband. We noted no difference in their performance on the verbal fluency task. Qualitative evaluation of the structural images by a radiologist blind to subject status revealed no structural abnormalities. In the right-handed subject, we saw a significant activation of the left fronto-parietal cortex and the right cerebellar hemisphere (left precentral gyrus: mean signal change: 0.76%, number of activated pixels: #8553, the left middle and inferior frontal cortex: 0.67%, #4044 and 0.75%, #1394, left SMA: 0.81% and #1061, the left superior and inferior parietal cortex: 0.41%, #1620 and 0.49, #717 and the right cerebellar hemisphere: 0.40% and #1191) (Fig. 1). In the left-handed proband we detected a right frontotemporo-parietal cerebral activation, along with a contralateral activation of the left cerebellar hemisphere (right precentral gyrus: mean signal change 0.89%; number of activated pixels: #10118, the right middle and inferior frontal cortex: 0.88%, #11403 and 0.62%, #3978, right SMA: 0.62% and #995, right superior temporal cortex: 0.63% and #3123, right superior and inferior parietal cortex: 1.80%,
Fig. 1. fMRI results in the right-handed person demonstrating the crosswise activation of the cerebral cortex and the cerebellum. There is a significant BOLD-response at position z ¼ 34 (left side of the figure) of the left frontal and parietal cortex and at position z ¼ -27 (right side lower field) of the right cerebellar hemisphere. The averaged time course of the cerebellar BOLD response (dark red) shows a correlation of 0.49 ðP , 0:0001Þ with the reference function (black) and a mean signal change of 0.40% (right upper field).
P. Hubrich-Ungureanu et al. / Neuroscience Letters 319 (2002) 91–94
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Fig. 2. fMRI results of the left-handed person demonstrating the crosswise activation of the cerebral cortex and the cerebellum. There is a significant BOLD-response at position z ¼ 35 (left side of the figure) of the right frontal and parietal cortex and at position z ¼ 235 (right side lower field) of the left cerebellar hemisphere. The averaged time course (dark red) of the cerebellar BOLD response shows a correlation of 0.45 ðP , 0:0001Þ with the reference function (black) and a mean signal change of 0.48% (right upper field).
#8770 and 1.63%, #7798 and the left cerebellar hemisphere: 0.48%, and #3315) (Fig. 2). Both volunteers show nearly the same although mirrorimaged activation of a complex network involving supraand infratentorial centers. Our data clearly demonstrate that a change of lateralization in the cerebrum is followed by a change of lateralization in the cerebellum. The only difference was that in the left-handed volunteer the activation of all regions was much stronger than in the right-handed volunteer, but interindividual differences in cluster size and mean signal change are known for different fMRI paradigms involving simple motor tasks as well as cognitive tasks. Silent verbalization might not be wholly linguistic but may also include motor planning correlating with activation of the prefrontal gyrus and the supplementary motor area. Both volunteers only show unilateral activation of the prefrontal gyrus in the language dominant hemisphere but not of other higher order motor areas. Thus, the argument of motor planning does not invalidate the finding of crossed connections between hemispheres and cerebellum. To our knowledge, this is the first fMRI study demonstrating a change in the lateralized organization of the cerebellum resulting from a change in hemispheric language dominance. In healthy volunteers showing different language dominance we were able to demonstrate variations in the side of cerebellar activation in a silent verbal fluency task. Though this case study needs to be reproduced in other asymmetrical organized tasks, it may provide new information about the function and organization of the cerebellum. In line with the anatomical background of crossed reciprocal connections between the cerebellum and the hemispheres, the cerebellar side in support of higher cognitive
function varies depending on the cerebral dominance. Previous studies also support this hypothesis. A verbal fluency MRI-paradigm in right-handed persons showed a constant activation of the right cerebellum [18]. Visualspatial deficits were described following excision of left cerebellar hemisphere tumors [20], whereas impaired linguistic processing was seen in patients with right cerebellar infarction [17]. Thus, we conclude that in addition to the concept of cerebellar participation in higher cognitive function and topographic organization, the cerebellum, similar to the cerebral hemispheres, also shows both lateralization and asymmetric organization in supporting these functions. This study was supported by the ‘Forschungs-Schwerpunktprogramm Baden-Wu¨ rttemberg’. [1] Akshoomoff, N.A., Courchesne, E. and Townsend, J., Attention coordination and anticipatory control, Int. Rev. Neurobiol., 41 (1997) 575–598. [2] Andreasen, N.C., Paradiso, S. and O’Leary, D.S., ‘Cognitive dysmetria’ as an integrative theory of schizophrenia: a dysfunction in cortical–subscortical–cerebellar circuitry, Schizophr. Bull., 24 (1998) 203–218. [3] Bandettini, P.A., Wong, E.C., Hinks, R.S., Tikofsky, R.S. and Hyde, J.S., Time course EPI of human brain function during task activation, Magn. Reson. Med., 25 (1992) 390–397. [4] Decety, J., Sjo¨ holm, H., Ryding, E., Stenberg, G. and Ingvar, D.H., The cerebellum participates in mental activity: tomographic measurement of regional cerebral blood flow, Brain Res., 535 (1990) 313–317. [5] Goebel, R., Brainvoyager: a program for analysing and visualising functional and structural MRI data set, Neuroimage, 3 (1996) S604. [6] Kim, S.G., Ugurbil, K. and Strick, P.L., Activation of a cerebellar output nucleus during cognitive processing, Science, 265 (1994) 949–951.
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[7] Knecht, S., Dra¨ ger, B., Deppe, M., Bobe, L., Lohmann, H., Flo¨ el, A., Ringelstein, E.B. and Henningsen, H., Handedeness and hemispheric dominance in healthy humans, Brain, 123 (2000) 2512–2518. [8] Leiner, H.C., Leiner, A.L. and Dow, R.S., Does the cerebellum contribute to mental skills, Behav. Neurosci., 100 (1986) 443–454. [9] Ogawa, S., Lee, T.M., Kay, A.R. and Tank, D.W., Brain magnetic resonance imaging with contrast dependent on blood oxygenation, Proc. Natl Acad. Sci. USA, 87 (1990) 9868–9876. [10] Oldfield, R.C., The assessment and analysis of handedness: the Edinburgh inventory, Neuropsychologia, 9 (1971) 97– 113. [11] Peterson, S.E., Fox, P.T., Posner, M.I., Mintun, M. and Raichle, M.E., Positron emission tomographic studies of the cortical anatomy of single word processing, Nature, 331 (1988) 585–589. [12] Ramier, A.M. and Hacaen, S.C., Role respecto des atteintes frontales et de la lateralisation leasionelle dans deficits de la fluence verbale, Rev. Neurol., 123 (1970) 17–22. [13] Rees, G.E., Frackowiak, R.S.J. and Frith, C.D., Cerebellar activity is modulated in two ways by attention, Neuroimage, 5 (1997) S86.
[14] Schmahmann, J.D., An emerging concept, the cerebellar contribution to higher function, Arch. Neurol., 48 (1991) 1178–1187. [15] Schmahmann, J.D. and Pandya, D.N., Prefrontal cortex projections to the basilar pons in rhesus monkeys: implications for the cerebellar contribution to higher functions, Neurosci. Lett., 199 (1995) 175–178. [16] Schmahmann, J.D. and Sherman, J.C., The cerebellar cognitive affective syndrome, Brain, 121 (1998) 561–579. [17] Silveri, M.C., Leggio, M.G. and Molinari, M., The cerebellum contributes to linguistic production: a case of agrammatic speech following right cerebellar lesion, Neurology, 44 (1994) 2047–2050. [18] Schloesser, R., Hutchinson, M., Joseffer, S., Rusinek, H., Saarimaki, A., Stevenson, J., Dewey, S.L. and Brodie, J.D., Functional magnetic resonance imaging of human brain activity in a verbal fluency task, J. Neurol. Neurosurg. Psychiatry, 64 (1998) 492–498. [19] Talairach, J. and Torneaux, P., Co-planar stereotactic atlas of the human brain, Thieme, Stuttgart, 1988. [20] Wallesch, C.W. and Horn, A., Long term effects of cerebellar pathology on cognitive function, Brain Cogn., 14 (1990) 19– 25.
Lateralized organization of the cerebellum in a silent verbal fluency task: a functional magnetic resonance imaging study in healthy volunteers Petra Hubrich-Ungureanu*, Nina Kaemmerer, Fritz A. Henn, Dieter F. Braus Central Institute of Mental Health (ZI), NMR-Research, P.O. Box 122 120, D-68072, Mannheim, Germany Received 31 October 2001; received in revised form 7 December 2001; accepted 7 December 2001
Abstract Functionally, the cerebellum is not only involved in motor control but is also thought to influence higher cognitive function including language. Anatomical data would suggest crossed reciprocal connections between the cerebellum and higher order cortical association areas. In the following study, one left- and one right-handed female volunteer underwent functional magnetic resonance imaging in a conventional block design. Regions of activation were detected after performance of a silent verbal fluency task inside the scanner. In the right-handed volunteer we found an activation of the left fronto-parietal cortex and the right cerebellar hemisphere, while in the left-handed volunteer the activation was seen in the right fronto-parieto-temporal cortex and the left cerebellar hemisphere. These initial results demonstrate that cerebellar activation is contralateral to the activation of the frontal cortex even under conditions of different language dominance. They provide evidence for the hypothesis of a lateralized organization of the cerebellum crossed to the cerebral hemispheres in supporting higher cognitive function. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cerebellum; Higher cognitive function; Language; Handedness; Lateralization; Schizophrenia; Functional magnetic resonance imaging
Traditional neurologic teaching suggests that functionally the cerebellum is mainly involved in motor control, although this view has been increasingly challenged over the past decade. Phylogenetically, the neocerebellum developed and enlarged parallel to the newer cerebral association areas [8]. Strong, crossed reciprocal connections to higher order cerebral association areas have been shown, especially to the prefrontal cortex [14]. The afferent pathway is connected via the pons, the efferent pathway via the thalamus [15]. A growing body of empirical data, largely derived from functional imaging studies, shows the cerebellum’s involvement in a number of higher cognitive functions. In positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies, the participation of the cerebellum has been seen in different cognitive tasks associated with memory, language, attention, mental imagery and problem solving [1,4,6,11,13]. * Corresponding author. Tel.: 149-621-1703-205; fax: 149-6211703-673. E-mail address: [email protected] (P. Hubrich-Ungureanu).
In patients with cerebellar lesions cognitive, affective and behavioral deficits have been observed in addition to motor deficits, a cluster of symptoms now known as the cerebellar cognitive affective syndrome [16]. The cerebellum is also regarded as a node in altered circuits underlying some mental diseases. Thought disorders in schizophrenia are assumed to be a symptom of cerebellar dysfunction called ‘cognitive dysmetria’. Finally, there is a growing body of evidence suggesting that the disturbed circuit underlying schizophrenia consists of the frontal cortex, the thalamus and the cerebellum (CCTCC) [2]. The asymmetric organization of the cerebral cortex is well known. In right-handed individuals, language dominance is mostly represented in the left hemisphere, whereas in approximately 27% of strong left-handed persons the functional dominance of the hemispheres is reversed [7]. This leads to the hypothesis that there might also be a lateralized functional organization of the cerebellum, which shows a crosswise link to the hemispheres in the modulation of higher cognitive functions. To contribute to this question, the present case study used
0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 1) 02 56 6- 6
92
P. Hubrich-Ungureanu et al. / Neuroscience Letters 319 (2002) 91–94
verbal fluency, a well-established paradigm for testing language function [12] in combination with fMRI [9]. We examined two healthy females, one being right- and the other left-handed. Neither had a history of drug abuse, they were mentally normal and had no family history of psychiatric illness. Prior to the fMRI examination handedness was determined with the Edinburgh handedness inventory [10]. For performance control volunteers had been asked to generate words aloud three times prior to data acquisition (S,A,B). During fMRI, verbal fluency was tested by silent performance of the task. The silent condition was chosen to reduce motor artifacts and to assure that the cerebellar activation was indeed due to verbal generation and not articulation. Volunteers were asked to generate words beginning with letters, which had previously been sounded to them over the intercom. The letters for the seven activation conditions were E, F, G, U, W, R and P. After scanning, they were then asked to give examples of the words they had generated in the silent condition and to estimate the amount of words they had generated in each category. During the resting condition volunteers simply relaxed. Written informed consent had been obtained prior to the examination and the study had been approved by the local ethics committee. Imaging was performed on a standard clinical 1.5 T MRI Scanner (Siemens Visionw). For fMRI a standard EPISequence (TE ¼ 66 ms, a ¼ 908, repetition time every 4 s) with an in plane resolution of 64 £ 64 pixels (28 slices, 4 mm thickness, gap 1 mm, FoV 220 mm) was used. For anatomical reference a 3D Magnitization Prepared Rapid Gradient Echo (MPRAGE) image data set was acquired. fMRI slices were oriented axially parallel to the AC–PC line according to
Talairach and Tournoux [19]. Each functional T2* slice was imaged 140 times over a total period of 560 s. Data analysis was performed using custom software (Brainvoyager 4.2) [5]. Prior to statistical analysis the time series of functional images was aligned for each slice in order to minimize the effects of head movement. In order to statistically evaluate the differences between stimulation conditions cross-correlation analysis was applied. For the computation of correlation maps, the stimulation protocol served as a box car reference function reflecting the temporal sequence of stimulation and control conditions [3]. For the actual study, we recruited a 33 and a 35-year-old woman, the former right- and the latter left-handed. The degree of handedness was 100 in the right-handed and 275 in the left-handed proband. We noted no difference in their performance on the verbal fluency task. Qualitative evaluation of the structural images by a radiologist blind to subject status revealed no structural abnormalities. In the right-handed subject, we saw a significant activation of the left fronto-parietal cortex and the right cerebellar hemisphere (left precentral gyrus: mean signal change: 0.76%, number of activated pixels: #8553, the left middle and inferior frontal cortex: 0.67%, #4044 and 0.75%, #1394, left SMA: 0.81% and #1061, the left superior and inferior parietal cortex: 0.41%, #1620 and 0.49, #717 and the right cerebellar hemisphere: 0.40% and #1191) (Fig. 1). In the left-handed proband we detected a right frontotemporo-parietal cerebral activation, along with a contralateral activation of the left cerebellar hemisphere (right precentral gyrus: mean signal change 0.89%; number of activated pixels: #10118, the right middle and inferior frontal cortex: 0.88%, #11403 and 0.62%, #3978, right SMA: 0.62% and #995, right superior temporal cortex: 0.63% and #3123, right superior and inferior parietal cortex: 1.80%,
Fig. 1. fMRI results in the right-handed person demonstrating the crosswise activation of the cerebral cortex and the cerebellum. There is a significant BOLD-response at position z ¼ 34 (left side of the figure) of the left frontal and parietal cortex and at position z ¼ -27 (right side lower field) of the right cerebellar hemisphere. The averaged time course of the cerebellar BOLD response (dark red) shows a correlation of 0.49 ðP , 0:0001Þ with the reference function (black) and a mean signal change of 0.40% (right upper field).
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Fig. 2. fMRI results of the left-handed person demonstrating the crosswise activation of the cerebral cortex and the cerebellum. There is a significant BOLD-response at position z ¼ 35 (left side of the figure) of the right frontal and parietal cortex and at position z ¼ 235 (right side lower field) of the left cerebellar hemisphere. The averaged time course (dark red) of the cerebellar BOLD response shows a correlation of 0.45 ðP , 0:0001Þ with the reference function (black) and a mean signal change of 0.48% (right upper field).
#8770 and 1.63%, #7798 and the left cerebellar hemisphere: 0.48%, and #3315) (Fig. 2). Both volunteers show nearly the same although mirrorimaged activation of a complex network involving supraand infratentorial centers. Our data clearly demonstrate that a change of lateralization in the cerebrum is followed by a change of lateralization in the cerebellum. The only difference was that in the left-handed volunteer the activation of all regions was much stronger than in the right-handed volunteer, but interindividual differences in cluster size and mean signal change are known for different fMRI paradigms involving simple motor tasks as well as cognitive tasks. Silent verbalization might not be wholly linguistic but may also include motor planning correlating with activation of the prefrontal gyrus and the supplementary motor area. Both volunteers only show unilateral activation of the prefrontal gyrus in the language dominant hemisphere but not of other higher order motor areas. Thus, the argument of motor planning does not invalidate the finding of crossed connections between hemispheres and cerebellum. To our knowledge, this is the first fMRI study demonstrating a change in the lateralized organization of the cerebellum resulting from a change in hemispheric language dominance. In healthy volunteers showing different language dominance we were able to demonstrate variations in the side of cerebellar activation in a silent verbal fluency task. Though this case study needs to be reproduced in other asymmetrical organized tasks, it may provide new information about the function and organization of the cerebellum. In line with the anatomical background of crossed reciprocal connections between the cerebellum and the hemispheres, the cerebellar side in support of higher cognitive
function varies depending on the cerebral dominance. Previous studies also support this hypothesis. A verbal fluency MRI-paradigm in right-handed persons showed a constant activation of the right cerebellum [18]. Visualspatial deficits were described following excision of left cerebellar hemisphere tumors [20], whereas impaired linguistic processing was seen in patients with right cerebellar infarction [17]. Thus, we conclude that in addition to the concept of cerebellar participation in higher cognitive function and topographic organization, the cerebellum, similar to the cerebral hemispheres, also shows both lateralization and asymmetric organization in supporting these functions. This study was supported by the ‘Forschungs-Schwerpunktprogramm Baden-Wu¨ rttemberg’. [1] Akshoomoff, N.A., Courchesne, E. and Townsend, J., Attention coordination and anticipatory control, Int. Rev. Neurobiol., 41 (1997) 575–598. [2] Andreasen, N.C., Paradiso, S. and O’Leary, D.S., ‘Cognitive dysmetria’ as an integrative theory of schizophrenia: a dysfunction in cortical–subscortical–cerebellar circuitry, Schizophr. Bull., 24 (1998) 203–218. [3] Bandettini, P.A., Wong, E.C., Hinks, R.S., Tikofsky, R.S. and Hyde, J.S., Time course EPI of human brain function during task activation, Magn. Reson. Med., 25 (1992) 390–397. [4] Decety, J., Sjo¨ holm, H., Ryding, E., Stenberg, G. and Ingvar, D.H., The cerebellum participates in mental activity: tomographic measurement of regional cerebral blood flow, Brain Res., 535 (1990) 313–317. [5] Goebel, R., Brainvoyager: a program for analysing and visualising functional and structural MRI data set, Neuroimage, 3 (1996) S604. [6] Kim, S.G., Ugurbil, K. and Strick, P.L., Activation of a cerebellar output nucleus during cognitive processing, Science, 265 (1994) 949–951.
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[7] Knecht, S., Dra¨ ger, B., Deppe, M., Bobe, L., Lohmann, H., Flo¨ el, A., Ringelstein, E.B. and Henningsen, H., Handedeness and hemispheric dominance in healthy humans, Brain, 123 (2000) 2512–2518. [8] Leiner, H.C., Leiner, A.L. and Dow, R.S., Does the cerebellum contribute to mental skills, Behav. Neurosci., 100 (1986) 443–454. [9] Ogawa, S., Lee, T.M., Kay, A.R. and Tank, D.W., Brain magnetic resonance imaging with contrast dependent on blood oxygenation, Proc. Natl Acad. Sci. USA, 87 (1990) 9868–9876. [10] Oldfield, R.C., The assessment and analysis of handedness: the Edinburgh inventory, Neuropsychologia, 9 (1971) 97– 113. [11] Peterson, S.E., Fox, P.T., Posner, M.I., Mintun, M. and Raichle, M.E., Positron emission tomographic studies of the cortical anatomy of single word processing, Nature, 331 (1988) 585–589. [12] Ramier, A.M. and Hacaen, S.C., Role respecto des atteintes frontales et de la lateralisation leasionelle dans deficits de la fluence verbale, Rev. Neurol., 123 (1970) 17–22. [13] Rees, G.E., Frackowiak, R.S.J. and Frith, C.D., Cerebellar activity is modulated in two ways by attention, Neuroimage, 5 (1997) S86.
[14] Schmahmann, J.D., An emerging concept, the cerebellar contribution to higher function, Arch. Neurol., 48 (1991) 1178–1187. [15] Schmahmann, J.D. and Pandya, D.N., Prefrontal cortex projections to the basilar pons in rhesus monkeys: implications for the cerebellar contribution to higher functions, Neurosci. Lett., 199 (1995) 175–178. [16] Schmahmann, J.D. and Sherman, J.C., The cerebellar cognitive affective syndrome, Brain, 121 (1998) 561–579. [17] Silveri, M.C., Leggio, M.G. and Molinari, M., The cerebellum contributes to linguistic production: a case of agrammatic speech following right cerebellar lesion, Neurology, 44 (1994) 2047–2050. [18] Schloesser, R., Hutchinson, M., Joseffer, S., Rusinek, H., Saarimaki, A., Stevenson, J., Dewey, S.L. and Brodie, J.D., Functional magnetic resonance imaging of human brain activity in a verbal fluency task, J. Neurol. Neurosurg. Psychiatry, 64 (1998) 492–498. [19] Talairach, J. and Torneaux, P., Co-planar stereotactic atlas of the human brain, Thieme, Stuttgart, 1988. [20] Wallesch, C.W. and Horn, A., Long term effects of cerebellar pathology on cognitive function, Brain Cogn., 14 (1990) 19– 25.