NeuroImage 44 (2009) 1369–1379

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NeuroImage j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y n i m g

Distinct striatal regions for planning and executing novel and automated movement sequences J. Jankowski ⁎, L. Scheef, C. Hüppe, H. Boecker FE Funktionelle Neurobildgebung, Experimentelle Radiologie, Radiologische Universitätsklinik, Rheinische Friedrich-Wilhelms-Universität Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany

a r t i c l e

i n f o

Article history: Received 20 June 2008 Revised 26 August 2008 Accepted 24 October 2008 Available online 14 November 2008 Keywords: Motor control Movement Motor planning Event related fMRI Basal ganglia associative loop Caudate Putamen

a b s t r a c t The basal ganglia-thalamo-cortical circuits are viewed as segregated parallel feed back loops crucially involved in motor control, cognition, and emotional processing. Their role in planning novel, as compared to overlearned movement patterns is as yet not well defined. We tested for the involvement of the associative striatum (caudate/anterior putamen) in the generation of novel movement patterns, which is a critical cognitive requirement for non-routine motor behavior. Using event related functional MRI in 14 righthanded male subjects, we analyzed brain activity in the planning phase of four digit finger sequences. Subjects either executed a single overlearned four digit sequence (RECALL), or self-determined four digit sequences of varying order (GENERATE). In both conditions, RECALL and GENERATE, planning was associated with activation in mesial/lateral premotor cortices, motor cingulate cortex, superior parietal cortex, basal ganglia, insula, thalamus, and midbrain nuclei. When contrasting the planning phase of GENERATE with the planning phase of RECALL, there was significantly higher activation within this distributed network. At the level of the basal ganglia, the planning phase of GENERATE was associated with differentially higher activation located specifically within the associative striatum bilaterally. On the other hand, the execution phase during both conditions was associated with a shift of activity towards the posterior part of the putamen. Our data show the specific involvement of the associative striatum during the planning of nonroutine movement patterns and illustrate the propagation of activity from rostral to dorsal basal ganglia sites during different stages of motor processing. © 2008 Elsevier Inc. All rights reserved.

Introduction Nearly every aspect of motor behavior is composed of multiple individual movement elements arranged in a sequential fashion. The order and timing of this sequential arrangement needs to be constantly adapted and modified depending on situational requirements and varying motor context. Recent neuroimaging studies using event-related functional magnetic resonance imaging (fMRI) have provided evidence that the relevant brain regions for planning sequential procedures can be dissociated from those directly involved in execution. Planning-related brain activity, preceding executionrelated activity, has been demonstrated in different cortical regions, in particular superior parietal, mesial and lateral premotor, and cingulate motor areas (Cunnington et al., 2002, 2003, 2005; Weilke et al., 2001). More recently, subcortical activity attributed to motor planning phases preceding sequential tasks could be identified with eventrelated fMRI (Boecker et al., 2008; Elsinger et al., 2006). Using region of interest (ROI) based analyses, Elsinger et al. were able to identify enhanced anterior putamen activity when externally specified finger ⁎ Corresponding author. Fax: +49 228 287 14457. E-mail address: [email protected] (J. Jankowski). 1053-8119/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2008.10.059

sequences were held in memory for delayed subsequent execution (Elsinger et al., 2006), and our recent work, comparing self-initiated with externally triggered performance of one unique automated motor sequence, further highlighted the role of the contralateral anterior putamen for determining when to initiate movements (Boecker et al., 2008). Even more anteriorly located parts of the basal ganglia (caudate/adjacent anterior putamen), corresponding to the associative striatum (Nakano et al., 2000; Postuma and Dagher, 2006), are attributed to reasoning (Melrose et al., 2007), cognitive planning required to perform set-shifts (Monchi et al., 2006), or voluntary motor selection processes (Gerardin et al., 2004). Indeed, when voluntarily selecting with which body side to execute a simple button press, movement was associated with bilateral activation of the caudate nucleus, while preparing the movement was associated with anterior putamen activity, and execution with posterior putamen activity (Gerardin et al., 2004). In this study, the aim was to further specify the functional role of the different basal ganglia territories in planning sequential movements. Rather than interrogating activation patterns related to determining effector sides, we specifically intended to characterize basal ganglia subregional recruitments required for planning novel (none-routine), as compared to overlearned (routine) movement

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patterns, which is an important component of adaptive motor behavior. A sequence generation task allowed us to deduce brain activity during the pre-movement phases and to directly compare activity during the planning of novel sequences with activity during the recall of one overlearned sequence. For this cognitive motor planning operation, we hypothesized specific involvement of the associative striatum (caudate nucleus/adjacent anterior putamen), in contrast to more posteriorly located putamen activation during the recall of overlearned movements. We further hypothesized posterior putamen activation during the execution phase of both motor conditions. An important premise of this study on motor sequence planning was that no explicit or implicit motor learning, evidenced in decreases of response-times, execution times and/or sequencing errors would occur during the course of the sequence generation task in the scanner. Motor learning was considered as an important confound since previous imaging studies (Bapi et al., 2006; Floyer-Lea and Matthews, 2004; Hikosaka et al., 2002; Jueptner et al., 1997; Lehericy et al., 2005; Poldrack et al., 2005; Toni et al., 1998) have unambiguously shown motor learning-associated basal ganglia activation shifts along a rostro-dorsal gradient. Methods Subjects 17 healthy male volunteers without a history of neurological or psychiatric disorder were enrolled in the study after informed and written consent. The study was approved by the local Ethics Committee of the University Hospital, University of Bonn, and in compliance with national legislation and the Code of Ethical Principles for Medical Research Involving Human Subjects of the World Medical Association (Declaration of Helsinki). Two measurements had to be excluded due to incomplete data acquisition (scan abortion) and one due to violation of task instructions despite previous training (see below). This resulted in a total sample size of 14 (mean age 26.7 ± 5.9 years, range 19–41 years) right-handed (mean laterality quotient = 0.96, range 0.86 to 1.00) male subjects, according to the Edinburgh Handedness Inventory (Oldfield, 1971). Task instruction and training Before the fMRI measurements, all subjects were familiarized with the experimental procedure and instructed to perform four-digit finger sequences with their left and right hands at a fluent and comfortable

pace. Besides sequences that could be freely determined by the subjects (GENERATE), one particular sequence was specified (RECALL; see below). Subsequently, both, the self generation of sequences and the execution of the specified sequence were practiced during a training session, until a consistent performance with a minimum of errors (b5%) was achieved. Errors were defined as follows: less or more than four button presses per sequence, pressing the same button more than once per sequence or wrong effector side. For the RECALL condition, in addition any sequence of button presses other than the predefined sequence was considered an error, as well as any type of button press during the rest condition. Before the experiment started, subjects additionally rehearsed the tasks in the scanner. Paradigm The tasks consisted of finger sequences of four button presses, which were externally triggered by a visual cue for each individual trial. All sequences had to involve the index finger, the middle finger, the ring finger, and the little finger. Two major conditions were distinguished: an overlearned recall condition (RECALL), where subjects had to press the buttons in a predefined sequential order: index finger, ring finger, middle finger, and little finger; and a nonroutine generate condition (GENERATE), where subjects had to generate novel orders of button presses at the beginning of each individual trial. Subjects were instructed to vary the sequences from trial to trial. Sequences had to be performed with either the left or the right hand, as instructed, resulting in four different movement conditions: RECALLR, RECALLL, GENERATER and GENERATEL. For all conditions, each experimental trial consisted of the following elements (Fig. 1A): 1) A two seconds instruction (I), defined as the time during which a text was displayed, specifying the sequence mode (RECALL, GENERATE or REST) and, the effector side (R or L) (Fig. 1C). 2) An eight seconds time frame, during which the movement had to be started after a visual cue (see below). The available time was indicated by a horizontally oriented, continuously shrinking red bar, which was displayed at the centre position (Fig. 1C). 3) A 500 milliseconds color change of the red bar to green and back, which served as cue for the subject to start the finger sequence. This color change was programmed to appear at pseudorandomized time points during the display of the shrinking red bar (mean 4.0 s, range 0.6 to 7.6 s after onset of the red bar). To ensure,

Fig. 1. Graphical display of the experimental paradigm. (A) Time scale and order of successive elements of one trial, which were identical for all conditions. The small black arrow (movement) below the bar indicates the execution of the finger sequence, with its onset delayed by the response time in respect to the onset of the cue (i.e. change of the color from red to green). (B) Arrows indicate the two phases modeled for data analysis in SPM5, a pre-movement “planning” (PLAN-) and a movement (EXE-) phase and are aligned with the trial elements shown above in A. (C) Illustration of display seen by the subject during one trial. Instructions were presented in German (background color blue, instruction and fixation cross yellow, color bar bright red and cue bright green).

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that subjects could complete the sequence when the movement was initiated late without interfering with the following instruction, the paradigm was programmed such, that in the case of late movement initiation the color bar was followed by an intertrial interval of at least 1.5 s. In addition, data was later checked for an overlap of movement and instruction, and these very rare cases (b0.5%) were modeled as errors but not considered as errors in the behavioral data analysis. For the rest condition (REST), the subjects were instructed to observe the bar and the random color change without movement. There was no further subdivision of the rest condition. Each of the five experimental conditions occurred 30 times and all 150 trials were arranged in random order and separated by variable intertrial intervals ranging from 0.12 to 5.84 s (mean 2.86 s, equally distributed within each session) during which a fixation cross was displayed (Figs. 1A, C). The duration of all consecutive trials was 32 min. Subjects were asked to attend to the visual display and to relax their nonmoving hand(s) during the whole measurement. All motor responses during task execution were recorded using two MR-compatible response keypads (LUMItouch, Photon Control Inc., Burnaby, BC, Canada). MRI procedures All stimuli were delivered using Presentation 9.81 (Neurobehavioral Systems, Albany, CA, USA) and projected on a semi translucent screen positioned outside the scanner at a distance of approximately 2 m from the scanner. Subjects viewed the projection screen via a mirror mounted on the head coil. Functional MRI was performed on a 3.0T Achieva whole body MRI (Philips Medical Systems, Best, The Netherlands) using an 8 channel SENSE head coil in quadrature mode (MRI-Devices) and a T2⁎weighted gradient echo (GE) single-shot EPI with the following sequence parameters: TE/TR/flip angle = 35 ms/2595 ms/90°, spatial resolution: 3.6 × 3.6 × 3.6 mm3. A total of 41 axial slices were recorded in interleaved ascending mode, which provided coverage of the entire brain (FOV: 230 × 230 × 147 mm3). In total, 800 volumes were acquired per fMRI-session. For all subjects, additional high-resolution structural images were acquired. The scan parameters were as follows: sequence-type MPRAGE, TE/TR/flip angle = 3.9 ms/7.7 ms/15°, matrix 256 × 256, FOV 256 × 256 × 180 mm3 (1 mm3 isotropic). Analysis of behavioral data The behavioral data (duration of movement, response time, and error rate) recorded during image acquisition were statistically analyzed for differences between conditions and behavioral parameters on single subject and group levels using a repeated measures analysis of variance (ANOVA) in SPSS 14.0 (Chicago, Illinois, USA). The within-subject factors movement conditions (GENERATE, RECALL) were analyzed for significant effects upon duration of movement, response time, and error rate. The response time was defined as the duration between the appearance of the color switch and the first button press. Subjects were instructed that there was no requirement to respond as fast as possible but rather to focus on accurate performance. The duration of movement was defined as the time between the first and the last button press. Again, subjects were instructed that there was no requirement to perform the sequence as fast as possible, but rather at a comfortable pace. MRI data analysis — preprocessing Pre-processing of the MRI data was performed with SPM5 (Wellcome Dept. of Imaging Neuroscience, London, UK). After slice time correction, all functional images were spatially realigned and

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unwarped to the first functional image to correct for head motion during the 800 image session. The realigned functional images were spatially normalized to the default EPI template in MNI space as provided by SPM5. After normalization, the data were interpolated to a voxel size of 3.0 × 3.0 × 3.0 mm3 and smoothed using an isotropic Gaussian kernel of 8 × 8 × 8 mm3. MRI data analysis — model estimation and statistics At the first level, the data were analyzed on a voxel-by-voxel basis using the principles of the general linear model (Friston et al., 1995). Within each trial, two phases (PLAN and EXE) were modeled as behaviorally defined epochs by specifying the onset and the duration (Fig. 1B): 1) A phase, during which pre-movement-planning of the sequences was performed (PLAN), consisting of the instruction and the variable phase between the onset of the red color bar and the first button press. 2) The execution phase (EXE), which was defined as the time between the first and the last button press. Consequently, the design matrix consisted of these two event types PLAN and EXE for the movement conditions and one phase for the rest condition. These event-types were modeled for the three conditions (RECALL, GENERATE, REST) as well as for both hands (R, L) separately, using the canonical hemodynamic response function as provided by SPM5, resulting in a total of 9 regressors of interest. A 128 s high pass filter was used to remove low-frequency noise. The error events were included in the model as regressors of no interest. Both phases (PLAN and EXE) were modeled as behaviorally defined epochs by specifying the onset and the duration, determined as described above. Modeling the durations was important to account for the wide range of the duration of the PLAN-phase (0.6 s to 7.6 s + 2 s instruction + response time). To account for possible activation changes between single trials caused by e.g. learning effects in the course of the session, a separate model was set up including time modulation (1st and 2nd order) for each movement condition as additional regressor. Since this did not reveal any relevant differences in activations in comparison to the simple model as described above, only data of the model without time modulation will be shown here. The analyses of the following functional contrasts were performed: 1) The pre-movement brain activity of the self-generated condition (GENERATEPLAN) and the recall condition (RECALLPLAN) compared to the baseline. 2) The movement brain activity of the self-generated condition (GENERATEEXE) and the recall condition (RECALLEXE) compared to the baseline. 3) The effect of self-generation during planning of sequences by comparing the PLAN-phase of the self-generated with the recall conditions (GENERATE PLAN N RECALL PLAN and RECALL PLAN N GENERATEPLAN). The respective contrasts from the single subject analyses were used for second-level random effects analyses and considered significant when surpassing a height threshold of p b 0.05 corrected for family wise errors (FWE-correction) for within-condition contrasts, and p b 0.01 corrected for false positive errors (FDR-correction; Genovese et al., 2002) for differential (between-condition) contrasts. For comparison of activated regions within the basal ganglia, we performed region of interest (ROI)-based analyses, using the Anatomical Automatic Labeling (AAL) based basal ganglia ROI (including bilateral pallidum, putamen and caudate nucleus) of the WFU PickAtlas GUI (Wake Forest

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University, Winston-Salem, NC, USA; http://www.ansir.wfubmc.edu). ROI analyses were thresholded at p b 0.05, FWE-corrected. Anatomical localization of the activation peaks was determined using the SPM Anatomy Toolbox 1.5 (Eickhoff et al., 2005) and for regions not covered by the toolbox, in addition using the AALtemplate included in the MRIcro software tool (Version 1.40.1, http:// www.sph.sc.edu/comd/rorden/, Chris Rorden, University of South Carolina, Columbia, SC, USA) based on MNI-coordinates. Results The focus of this report is on the relative difference in brain activation, when planning novel sequences is compared to recall of

automated motor routines. As we did not intend to analyze hemispheric effector-dependent differences, we will focus on the fMRI data related to the performance of the dominant right hand only. Therefore, if not stated otherwise, all data presented here refer to the right hand. Behavioral data On average, single subjects chose to execute 14 ± 4 of the 24 possible four-digit finger sequences during the GENERATE-condition (range: 5 to 20 different sequences per subject; Fig. 2A). Throughout all conditions and subjects, the mean duration of the PLAN-phase was 6.79 ± 0.11 s, with the mean values of single subjects ranging from 6.41 s to 7.05 s. Since the PLAN-phase consisted of: 1) the instruction, 2) the

Fig. 2. Behavioral data. (A) Relative occurrence of each of the 24 possible finger sequences with respect to the total of all correctly executed sequential movements during the generate (GENERATE) conditions. The numbers below the x-axis correspond to the finger sequence (top to bottom). (B, C, D: box-plots) Median of single subject means on group level (horizontal black line), interquartile range (box), extremes (vertical lines) and outliers (circles) of response times (B), duration of movement execution (C) and errors (D). For mean values and standard deviations see Results section.

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red color bar until the cue for movement onset and 3) the response time, differences between subjects solely resulted from differing response times (see Methods section and Fig. 1A). The average response time (GENERATE and RECALL) was 0.55 ± 0.10 s (range 0.15 to 1.48 s), 0.59 ±0.16 s (range 0.17 to 1.44 s) for GENERATE, and 0.53 ± 0.10 s (range 0.15 to 1.48 s) for RECALL. Multivariate testing for differences between conditions showed a significantly shorter response time during RECALL as compared to GENERATE at the level of p = 0.004 (F = 12.60; Fig. 2B). The average duration of movement execution (GENERATE and RECALL) was 1.29 ± 0.33 s (range 0.36 to 2.98 s), 1.40 ± 0.39 s (range 0.36 s to 2.98 s) for GENERATE, and 1.18 ± 0.29 s (range 0.54 to 2.10 s) for RECALL. Multivariate testing for differences between conditions showed a significantly faster performance during RECALL as compared to GENERATE at the level of p = 0.002 (F = 15.72; Fig. 2C). The number of erroneous trials per session (GENERATE and RECALL) was 4 ± 3 errors (range 0 to 9 errors), 2 ± 2 errors (range 0 to 7 errors) for GENERATE, and 1 ± 2 errors (range 1 to 4 errors) for RECALL. Multivariate testing for differences between conditions showed significantly higher error-rates during GENERATE as compared to RECALL at the level of p = 0.001 (F = 17.04; Fig. 2D). To detect “learning” or “habituation” effects during the scanning session, we performed a correlation analysis of the parameters “response time” and “duration of movement execution” for significant changes over

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time during the scanning session. For the GENERATE conditions, one subject revealed a significant decrease and one a significant increase of response times over the duration of the experiment. Within three of 14 subjects, we could detect a negative correlation between the duration of the four-digit finger sequence and the trial number. When performing a linear regression analysis in the subjects showing a correlation, the duration of movement execution decreased 33% (390 ms), 17% (220 ms) or 43% (250 ms) over the 30 trials. In spite of these substantial differences, even on the single subject level, we could not detect any relevant activation differences in the activations, when including these behavioral effects in the model (see Methods section). FMRI data Planning related activity The PLAN-phase of the generate-condition compared to baseline (GENERATEPLAN), was associated with significant activation of planning-related networks, including premotor-, superior and inferior parietal cortical regions, insula, and subcortically midbrain structures (subthalamic nucleus, red nucleus) and contralateral basal ganglia (p b 0.05, FWE-corrected; Fig. 3A, Table 1A). To illustrate the full extent of activations during the PLAN-phase, Fig. 3B is thresholded at p b 0.005, FDR-corrected. ROI-based analysis of the basal ganglia

Fig. 3. SPM-graphics based display of the activation clusters during the pre-movement (PLAN) phase, preceding the execution of the self-generated sequences (A and B; GENERATEPLAN) and the single overlearned sequence (C and D; RECALLPLAN). A and C are thresholded at p b 0.05, FWE-corrected, B and D are thresholded at p b 0.005, FDR-corrected to show the full extent of activations. Extent threshold (cluster size) k = 10. Note the higher and more extended activations and the more bilateral distribution of cortical activations of GENERATE (B) in comparison to RECALL (D), on both, the cortical (upper z = 45 slice) as well as the subcortical level (bottom z = 0 slice; basal ganglia). If not indicated otherwise, MNIcoordinates of sections are x = 0, y = 0, z = 0.

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Table 1 Activations during pre-movement phase (PLAN) A GENERATEPLAN compared to baseline Cortical regions

BA

K

T

Z

MNI x

y

z

Left

7 6 4 6 13 40 6 6

30 54 13 24 28 16 11

11.88 11.72 9.79 10.90 10.74 10.47 10.29 9.93

5.58 5.55 5.17 5.40 5.37 5.32 5.28 2.20

− 12 −24 −36 −9 −30 −39 −57 21

−72 −18 −15 0 21 − 42 3 −9

45 57 54 51 3 45 30 60

Subcortical regions

K

T

Z

MNI x

y

z

Left

99

11.12 9.99 9.03 10.59 9.21

5.44 5.22 5.00 5.34 5.04

− 12 − 12 −15 6 12

−18 −18 0 −15 −12

−6 3 −3 −9 −3

y

z

−15 −18 −15 −9

60 54 54 57

Right

Right

Superior parietal lobule Precentral gyrus Precentral gyrus Superior frontal gyrus (SMA) Anterior insular cortex Inferior parietal lobule Precentral gyrus Superior frontal gyrus

Subthalamic nucleus Thalamus Medial globus pallidus Red nucleus Subthalamic nucleus

12 27

B RECALLPLAN compared to baseline Cortical regions Left

Medial frontal gyrus Precentral gyrus Precentral gyrus Medial frontal gyrus (SMA)

BA

K

T

Z

MNI x

6 6 4 6

59

11.55 11.48 10.63 10.02

5.52 5.51 5.35 5.22

−18 −24 −36 −6

14

Activations during pre-movement motor planning phases (PLAN-phase). A: generatecondition (GENERATEPLAN) compared to baseline. B: recall-condition (RECALLPLAN) compared to baseline. Cortical and subcortical activations are listed separately (no subcortical activations for RECALLPLAN at the chosen threshold). Activation peaks are sorted by hemisphere (left or right) and by T-values (descending). Indented regions are local maxima within a spatially extended cluster (the voxel size K is listed once for each cluster). Analyses are thresholded at a height threshold of p b 0.05 corrected for family wise errors (FWE-correction) and an extent threshold of 10 voxel cluster size.

illustrates that the activation during the PLAN-phase was bilaterally distributed, the peaks being located in the caudate nucleus (head) and the adjacent parts of the anterior putamen (FWE-corrected; Fig. 6B, Table 3A). The PLAN-phase of the recall-condition compared to baseline (RECALLPLAN), was associated with significant activation of the contralateral mesial and lateral pre-motor regions extending into precentral gyrus (p b 0.05, FWE-corrected; Fig. 3C, Table 1B). At this threshold, no subcortical activations were observed. Viewing the extent of activations at p b 0.005, FDR-corrected (Fig. 3D) shows that the cortical activations are restricted to more contralateral pre-motor

and primary motor cortical regions, and within the basal ganglia are located more caudally, within mid-anterior portions of the putamen. This is confirmed by ROI analysis of the basal ganglia, where the extent of activation was substantially more restricted in comparison to GENERATEPLAN, located bilaterally in mid-putamen and the right anterior pallidum (BG-mask using WFU PickAtlas; p b 0.05, FWEcorrected; Fig. 6C, Table 3B). Motor-execution related activity In both, GENERATE and RECALL compared to baseline (GENERATEEXE and RECALLEXE), the activation during the EXE-phase was shifted from premotor/basal ganglia planning associated networks towards motor executive regions, with peak activations in primary motor cortex and anterior cerebellum (p b 0.05, FWE-corrected; Figs. 4A, B; Table 5A of Supplementary material). ROI-based analysis of the basal ganglia showed peak activity in bilateral putamen, with peaks in midposterior portions (p b 0.05, FWE-corrected; Figs. 6D, E; Table 5B of Supplementary material), illustrating the shift towards posterior regions as compared to the PLAN-phase. Differential planning related activity comparing the generate-with the recall-condition The whole-brain analysis comparing the activation during the PLAN-phase of GENERATE with the PLAN-phase of RECALL (GENERATEPLAN N RECALLPLAN) revealed differentially enhanced activity in bilateral frontoparietal cortical regions (p b 0.01, FDR-corrected; Fig. 5A, Table 2). At the subcortical level, there was relatively enhanced activation within the associative striatum, with peaks predominantly in caudate nucleus bilaterally (and contralateral anterior globus pallidus), which are likewise seen in ROI-based analyses of the basal ganglia (p b 0.05, FWE-corrected; Fig. 6F, Table 3C). Furthermore, there was significantly enhanced activity in the left thalamus and the ipsilateral cerebellum (ansiforme lobe, crus I). For the opposite contrast (RECALLPLAN N GENERATEPLAN), differentially enhanced activity during the PLAN-phase of RECALL could be detected in mid-frontoparietal regions (cingulate/precuneus and medial frontal gyrus), as well as in bilateral temporoparietal regions (p b 0.01, FDR-corrected; Fig. 5B, Table 4). However, we found no differential activity within the basal ganglia, neither in the whole brain nor in the basal ganglia ROI-based analysis (p b 0.01, FDRcorrected; ROI-based analysis, p b 0.05, FWE-corrected). Discussion There are two novel findings regarding the role of the basal ganglia in planning movement sequences. First, our data show differential

Fig. 4. SPM-graphics based display of the activation clusters during the movement (EXE) phase of the self-generated sequences (A; GENERATEEXE) and the single overlearned sequence (B; RECALLEXE), thresholded at p b 0.05, FWE-corrected and an extent threshold (cluster size) of k = 10. Note the preponderance of activation in motor executive regions in both, GENERATEEXE and RECALLEXE. Due to the less automated GENERATE (A) in comparison to RECALL (B), additional activation of motor areas, associated with the execution of more complex movements can be discerned. MNI-coordinates of sections are x = 0, y = 0, z = 0.

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Fig. 5. SPM-graphics based display of the differential activations during the pre-movement (PLAN) phase, preceding the execution. (A) Increased relative activation during the PLAN-phase of the generate-condition (GENERATEPLAN; self-generated sequences) when contrasted with the PLAN-phase of the recall-condition (RECALLPLAN; recall of single overlearned sequence). Note the differential activation within anterior regions of the basal ganglia (bottom z = 0 slice; anterior putamen and caudate) and fronto-parietal cortical networks (upper z = 45 slice). (B) Increased relative activation during the PLAN-phase of the recall-condition (RECALLPLAN) when contrasted with the PLAN-phase of the generate-condition (GENERATEPLAN). No differential effects can be detected within the basal ganglia (bottom z = 0 slice), however, this was the case in regions corresponding to the “default-motor-network”. Activations are thresholded at p b 0.01 FDR-corrected at an extent threshold (cluster size) of k = 10. If not indicated otherwise, MNI-coordinates of sections are x = 0, y = 0, z = 0.

loco-regional involvement of the basal ganglia depending on the cognitive requirements for generating movement sequences: planning of novel non-routine movement sequences (GENERATEPLAN) was associated with bilateral activations of the caudate nuclei (heads) and adjacent parts of the anterior putamen. This contrasted with the planning of overlearned movement sequence (RECALLPLAN), where the activation peaks were located more posteriorly within the midputamen. Second, we found a shift of activation at the level of the basal ganglia, namely from the associative striatum during the planning phase (GENERATEPLAN) to the posterior putamen during the execution phase (GENERATEEXE). This progression of neuronal activity along a rostro-caudal gradient (“cognitive” to “executive”) was also observed in the RECALL condition and corroborates current concepts of basal ganglia functional representations. Anatomically, the entire neocortex projects onto the basal ganglia (Delong et al., 1984; Romanelli et al., 2005): the caudate nucleus, putamen, and subthalamic nucleus constitute the input nuclei, while the internal segment of the globus pallidus (GPi) and the substantia nigra reticulata (SNr) serve as output nuclei (Afifi, 2003). The striatum has been grossly divided into three major functional zones, namely sensorimotor, associative and limbic zones (Nakano et al., 2000; Postuma and Dagher, 2006) receiving segregated input from motor, oculomotor, cognitive, and limbic cortical areas (Alexander and Crutcher, 1990; Alexander et al., 1986; Middleton and Strick, 2000). It has been shown that the anatomical segregation between “cognitive” (from prefrontal cortex) and “motor” inputs (from primary motor cortex) is maintained throughout different basal ganglia processing stages (Miyachi et al., 2006). While the cortico-striatal “cognitive” inputs from mesial and dorsal prefrontal areas (Yeterian and Pandya, 1991) project onto the caudate nucleus, those from preSMA project onto the caudate nucleus and the putamen subregion located rostral to the input zones from the caudal SMA and M1 forelimb regions (Inase et al., 1999; Kunzle, 1975). Even the corticostriatal inputs from M1 and SMA remain largely segregated, with only partial overlap within functionally distinct striatal, pallidal and

thalamic regions (Nakano et al., 2000; Nambu et al., 2002; Takada et al., 1998). The primary goal of our study was to identify the locoregional involvement of basal ganglia structures necessary for generating novel movement sequences (GENERATE), as compared to stereotyped behavior. We identified activations during the pre-motor planning phase in the caudate head and the adjacent anterior putamen, corresponding precisely to the associative striatum (Nakano et al., 2000; Postuma and Dagher, 2006). On the other hand, the activations in the RECALL condition were located more posteriorly in the middle putamen, similar to perfusion increases reported recently upon memory-guided performance of sequential finger movements (Garraux et al., 2005). Hence, our data clearly support a rostral-to-caudal functional subdivision within the striatum, which is in line with converging data from animal experiments: in monkeys trained to perform a sequential button-press task, injections of the GABA agonist muscimol in the middle-posterior putamen disrupts the execution of well-learned movement sequences, while new sequence learning is impaired after injections in the anterior caudate/putamen (Miyachi et al., 1997). Beyond data supporting a role of the caudate/ anterior putamen in motor learning (Miyachi et al., 2002, 1997; Winocur and Eskes, 1998), other animal studies have suggested a role in motor tasks demanding working memory (Kesner and Gilbert, 2006; Levy et al., 1997) and reward (Hikosaka et al., 1989; Hollerman et al., 1998) components. Moreover, sensorimotor planning is impaired in monkey experiments using intrastriatal 6-hydroxydopamine (6-OHDA) lesions as a model of dopamine depletion (Eslamboli et al., 2003). Human studies focusing on cognitive tasks like strategic planning (Dagher et al., 1999, 2001; Owen et al., 1996; van den Heuvel et al., 2003) or self-determined set-shifting (Monchi et al., 2006, 2007) have demonstrated specific caudate activations. Moreover, cognitive skill-learning (Beauchamp et al., 2003) or visuomotor skill learning (Beauchamp et al., 2003; Floyer-Lea and Matthews, 2004; Lehericy et al., 2005) are also compatible with an anterior to posterior

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Table 2 Differential activations during pre-movement phase (PLAN) GENERATEPLAN N RECALLPLAN Z

MNI x y

408a 8.57 7.10 5.19 4.59 480 8.49 6.87 6.93 6.16 382 8.36 6.66 5.36 5.27 96 7.19 6.42 5.24 4.57 43 6.66 4.79 112 6.61 5.97 5.27 4.42 78 5.68 5.42 5.22 5.16 4.60 15 7.70 189 7.42 6.51 222 7.30 6.08 31 6.49 43 6.30 5.55 57 5.93 17 5.07

4.88 4.46 3.75 3.48 4.86 4.39 4.41 4.14 4.83 4.32 3.83 3.79 4.49 4.24 3.78 3.47 4.32 3.57 4.30 4.07 3.79 3.39 3.96 3.85 3.77 3.74 3.48 4.64 4.56 4.27 4.53 4.11 4.26 4.19 3.91 4.05 3.70

−30 −27 − 48 −21 −24 −21 −9 −3 −33 −51 −33 −27 −45 −42 −45 −36 −36 −45 −9 −9 −15 −21 − 48 −60 −57 −42 −51 24 42 51 27 27 30 45 45 9 9

Subcortical regions

K

Z

MNI x y

Left

408a 6.81 6.66 5.58 5.12 42 5.11 4.82 4.72 149 7.28 6.92 6.25 4.81 30 6.48

Cortical regions

BA K

Left

13 47 13 11 6 6 32 6 40 2 7 19 9 48 44 9 10 46 7 7 18 7 44 6 4 9 6 23 40 2 6 8 7 45 45 7 32

Anterior insular cortex (claustrum) Inferior frontal gyrus (P. orbitalis) Anterior insular cortex Superior orbital gyrus Superior frontal gyrus Superior frontal gyrus Middle cingulate cortex Middle frontal gyrus (SMA) Inferior parietal lobule Inferior parietal lobule Superior frontal gyrus Middle occipital gyrus Middle frontal gyrus Inferior frontal gyrus (P. triangularis) Inferior frontal gyrus (P. opercularis) Middle frontal gyrus Middle frontal gyrus Inferior frontal gyrus (P. triangularis) Precuneus Precuneus Precuneus Superior parietal Lobule Inferior frontal gyrus (P. opercularis) Precentral gyrus Precentral gyrus Precentral gyrus Rolandic operculum Right Precuneus Inferior parietal lobule Inferior parietal lobule Middle frontal gyrus Middle frontal gyrus Middle occipital gyrus Middle frontal gyrus Middle frontal gyrus Precuneus Middle cingulate cortex

Lateral globus pallidus Caudate nucleus (body) Caudate nucleus (head) Caudate nucleus (body) Thalamus (ventral lateral nucleus) Thalamus (pulvinar) Thalamus Right Caudate nucleus (body) Caudate nucleus (head) Caudate nucleus (body) Medial globus pallidus Cerebellum crus 1

T

T

z

18 0 33 −6 12 0 15 −15 −6 54 6 54 18 39 12 48 −48 36 −33 39 − 60 45 − 63 33 30 33 30 24 21 33 42 36 57 12 48 6 − 63 51 −72 42 −72 33 −72 42 6 30 9 27 −3 36 3 36 6 15 −57 24 −39 45 − 36 57 6 51 9 60 −66 39 33 24 27 33 − 69 48 24 33

z

4.37 −15 3 −3 4.32 −15 12 12 3.92 −15 18 0 3.72 −9 3 15 3.72 −12 −12 9 3.59 −9 −24 9 3.54 −21 −18 3 4.52 15 15 12 4.40 15 12 6 4.17 12 6 12 3.58 12 3 −3 4.26 36 − 60 −33

Differential activations during pre-movement phases (PLAN-phase). Higher activation during generate-condition as compared to recall-condition (GENERATEPLAN N RECALLPLAN). Cortical and subcortical activations are listed separately. Data are presented as in Table 1. Analyses are thresholded at a height threshold of p b 0.01 corrected for false positive errors (FDR-correction) and an extent threshold of 10 voxel cluster size. a Although listed separately, cortical and subcortical activations belong to one continuous cluster.

organization of the basal ganglia. Regarding motor sequence learning, functional neuroimaging has demonstrated that regions of the associative loop are crucial for performance monitoring and learning of new motor sequences (Bapi et al., 2006; Hikosaka et al., 2002; Jueptner et al., 1997; Poldrack et al., 2005; Toni et al., 1998), whereas automated overlearned sequential movements require the sensorimotor putamen (Deiber et al., 1997; Grafton et al., 1992; Lehericy et

al., 2005). In our study, novel sequence generation was compared with recall of prelearnt sequences. However, the novel sequence generation task did not include a relevant explicit or implicit learning component and, indeed, our behavioral data clearly argue against relevant learning effects over the time of the MRI acquisition. Thus, the focus of this study is specifically on the necessary planning for generating novel sequences where the role of the associative striatum has not yet been studied sufficiently in motor tasks. Recently, Gerardin et al. studying visually instructed (non-sequential) button presses were able to show distinct bilateral caudate activations when subjects had to select their effector hand voluntarily (Gerardin et al., 2004). These findings also strongly indicate a role of the caudate nucleus/anterior putamen for self-determined action planning. Our data extend these findings in demonstrating that the anterior basal ganglia subregions are recruited in a task-dependent manner (GENERATE N RECALL). Moreover, the activity is clearly linked to the planning phase, corresponding to the period where motor plans are configured, rather than to the execution phase. Beyond the principal cognitive process of generating novel movement sequences by ordering individual motor components, working memory components (i.e. checking whether the order of the novel sequence is different from a previous one) cannot be excluded per se. We would like to point out, however, that we did not instruct our volunteers to attempt to generate every theoretically possible (N = 24) movement sequence. Rather, subjects were instructed to freely generate 4-digit sequences on a trial-by-trial basis and only to avoid strictly stereotype performance during the acquisition such as in the RECALL condition. In this context it is worth mentioning that only recently, imaging evidence has emerged for a differential role of the basal ganglia during pre-movement planning phases as compared to execution phases. Using event-related fMRI, Elsinger et al. studied BOLD signal timecourses during the pre-movement phase of internally and externally generated sequential movements differing in complexity. Planningrelated activity exceeded movement-related activity in the anterior putamen, indicating that “the basal ganglia specifically modulate motor planning processes that are engaged when formulating a plan of action before movement” (Elsinger et al., 2006). Recent work from our group has also been able to identify activity in the anterior putamen specifically related to the planning phase of a self-initiated, but otherwise automated, overlearned movement sequence (Boecker et al., 2008). Compared to these two studies, however, the activity during the PLAN-phase of self determined sequences (GENERATEPLAN) was located more anteriorly (head of caudate/adjacent anterior putamen). Thus, the presented data in healthy controls highlight the sub-regional functional specialization within the basal ganglia in a cognitive motor task where the neural basis of generating non-routine motor-sequences could be allocated in the PLAN-phase preceding movement onset. Likewise, clinical impairments have been described in tasks requiring planning, sequencing, and non-routine response selection after ischemic infarction of the caudate (Mendez et al., 1989; Petty et al., 1996; Troyer et al., 2004). Planning abilities are frequently impaired in patients with basal ganglia disorders: in non-demented Parkinson's disease (PD) patients with normal memory and visuospatial abilities, impairments in strategic planning have been identified (Taylor et al., 1986). Imaging studies in patients with PD have identified abnormal caudate activity in executive processes like planning (Dagher et al., 2001) and set-shifting (Monchi et al., 2007). Obsessive–compulsive disorder (OCD) has been shown to be associated with planning impairments in the Tower of London (TOL) task. OCD patients exhibit activation deficits in the caudate nucleus and in the dorsolateral prefrontal cortex (van den Heuvel et al., 2005). Interestingly, the binding potential of the D2 dopamine receptor ligand [11C]Raclopride in the right and left caudate nuclei correlated with the most ‘difficult’ (4-move) problems of the TOL, suggesting dopaminergic mechanisms in planning (Reeves et al., 2005).

J. Jankowski et al. / NeuroImage 44 (2009) 1369–1379

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Fig. 6. Region of interest (ROI) based analysis of the basal ganglia for sensitive detection foci of activations during the different phases and conditions. Display of axial sections spaced at 6 mm. First column (A): illustration of extent of basal ganglia mask (MNI-z-coordinates −6, 0, 6 and 12). During the PLAN-phase of the generate condition (B; GENERATEPLAN), basal ganglia activations are located within more anterior parts (anterior putamen and caudate) as compared to the recall (C; RECALLPLAN) and both movement conditions (D and E; GENERATEEXE and RECALLEXE). This finding is further confirmed by the differential contrast (F; GENERATEPLAN N RECALLPLAN). The inverse differential contrast (RECALLPLAN N GENERATEPLAN) is not shown, since there was no activation at the chosen threshold. Activations are thresholded at p b 0.05 FWE-corrected. Abbreviations: GEN =GENERATE, REC = RECALL.

The cortical areas identified in this study are highly consistent with extensive data on motor sequence control highlighting the role of the SMA and, in particular the pre-SMA (Boecker et al., 1998; Cunnington et al., 2002; Hikosaka et al., 2002; Picard and Strick, 1996), the rostral cingulate zone (Cunnington et al., 2002; Deiber et al., 1999; Jenkins et al., 2000), the DLPFC (Jenkins et al., 2000), the superior parietal cortex (Boecker et al., 1998), and the insula (Cunnington et al., 2002; Deiber et al., 1999; Jenkins et al., 2000). We show that the activity in these areas was significantly higher when directly comparing the generation of new sequences (GENERATE) with the recall of an overlearned sequence (RECALL), implicating higher levels of cognitive control for the former condition. It is also important to mention, that the different phases (PLAN, EXE) of the experimental trials were associated with characteristic cortical activation patterns: while the cortical activity during the planning phase showed bilateral involvement of frontoparietal regions (Fig. 3), cortical activity during the execution phase was shifted to primary sensori-motor regions (Fig. 4). Similar dissociations of cortical activation patterns have been described recently when comparing motor imagery and movement-related brain activity (Hanakawa et al., 2008). In that study on an instructed delay finger-tapping task, movement-predominant activity was found in the left central area, bilateral parieto-temporal junctions, and right anterior cerebellum, while imagery-predominant activity was found in left superior frontal sulcus, bilateral superior precentral sulcus, medial aspects of the superior frontal gyrus, and right occipital cortex. Our planning-phase related data are in line with previous imaging work highlighting the role of fronto-parietal networks for planning. For instance studies focusing on the Tower of London (TOL) task (Dagher et al., 1999; Owen et al., 1996) agree on the participation of the DLPFC and parieto-occipital regions (visuospatial system). More recent work using a parametric event-related fMRI version of the TOL task (van den Heuvel et al., 2003) found that the process of planning

Table 3 Activations during pre-movement phase (PLAN), basal ganglia ROI-analysis A GENERATEPLAN Basal ganglia regions

K

T

Z

MNI x

y

z

Left

159

9.03 6.86 6.82 6.43 8.65 7.97 5.77

5.00 4.38 4.37 4.24 4.90 4.72 3.99

−15 −15 − 18 − 33 12 12 27

0 18 15 6 3 15 21

−3 −3 9 −6 −3 0 −3

T

Z

MNI x

y

z

6.40 6.43 6.31 5.77

4.23 4.24 4.20 3.99

−21 18 33 33

0 6 6 12

3 −3 −3 0

T

Z

MNI x

y

z

6.81 6.66 7.28 6.92 6.25

4.37 4.32 4.52 4.40 4.17

−15 −15 15 15 12

3 12 15 12 6

−3 12 12 6 12

Right

Medial globus pallidus Caudate nucleus (head) Caudate nucleus (body) Claustrum Medial globus pallidus Caudate nucleus (head) Putamen

85 5

B RECALLPLAN Basal ganglia regions Left Right

Lateral globus pallidus Pallidum Putamen Putamen

K 32 35

C GENERATEPLAN N RECALLPLAN Basal ganglia regions Left Right

Lateral globus pallidus Caudate nucleus (body) Caudate nucleus (body) Caudate nucleus (head) Caudate nucleus (body)

K 10 7 36

Basal ganglia ROI-analysis of activations during pre-movement phase (PLAN-phase). A: Generate-condition (GENERATEPLAN) compared to baseline. B: Recall-condition (RECALLPLAN) compared to baseline. C: Higher activation during generate-condition as compared to recall-condition (GENERATEPLAN N RECALLPLAN). Data are presented as in Table 1. Analyses are thresholded at a height threshold of p b 0.05 corrected for family wise errors (FWE-correction) and an extent threshold of 5 voxel cluster size.

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J. Jankowski et al. / NeuroImage 44 (2009) 1369–1379

Appendix A. Supplementary data

Table 4 Differential activations during pre-movement phase (PLAN)

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.neuroimage.2008.10.059.

RECALLPLAN N GENERATEPLAN Cortical regions

BA

K

T

Z

MNI x y

Left

23 23 23 26 39 22 9 40 39 40 19 19 14–16 40 14–16 10

187

8.18 8.07 7.41 7.18 7.27 6.45 6.13 8.02 7.32 6.04 7.12 6.16 6.62 6.61 5.72 6.18

4.78 4.75 4.56 0.00 4.52 4.25 4.13 4.74 4.53 4.10 4.74 4.14 4.31 4.30 3.97 4.15

−6 0 0 6 − 51 −57 −9 63 51 60 27 27 39 42 36 6

Right Left

Right

Middle/posterior cingulate cortex Precuneus Precuneus Posterior cingulate cortex Middle temporal gyrus Middle temporal gyrus Superior medial gyrus Supra marginal gyrus Angular gyrus Angular gyrus Superior occipital gyrus Middle occipital gyrus Posterior insular cortex Rolandic operculum Posterior insular cortex Superior medial gyrus

58 12 48

12 16 12 10

−42 −51 −60 −45 −63 −54 42 −45 −51 −51 −81 −84 −9 −30 −27 66

z 36 36 21 27 21 21 45 39 36 30 27 18 −6 24 21 9

Differential activations during pre-movement phases (PLAN-phase). Higher activation during recall-condition as compared to generate-condition (RECALLPLAN N GENERATEPLAN). Only cortical activations are listed, since no subcortical activations occurred at the chosen threshold. Data are presented as in Table 1. Analyses are thresholded at a height threshold of p b 0.01 corrected for false positive errors (FDR-correction) and an extent threshold of 10 voxel cluster size.

correlated with activation of the right DLPFC (BA 9 and BA 46), bilateral premotor cortex (BA 6 and BA 8), bilateral precuneus (BA 7) and inferior parietal cortex (BA 40), left supplementary motor area (BA 32), right insular cortex, and bilateral striatum. This distributed activation pattern corresponds to a very large extent with our current findings. In the context of motor planning, as studied here, there are indications that the more abstract and spatial representations of future complex movements are conveyed by superior parietal regions, while the premotor and cingulate motor regions are more involved in initiating the required motor programs (Cavina-Pratesi et al., 2006). Interestingly, the direct comparison of RECALLPLAN N GENERATEPLAN revealed a relative deactivation of typical “default” brain networks (Buckner et al., 2008; Damoiseaux et al., 2006; Greicius et al., 2003; Raichle et al., 2001) in the cognitively demanding novel sequence generation condition, expanding previous studies that show task dependent deactivations in the default regions during active thinking (Esposito et al., 2006), working memory (Hampson et al., 2006), complex motor tasks (Boecker et al., 1998), and implicit motor sequence learning (Tamás Kincses et al., 2008). In conclusion, our study shows that different basal ganglia territories are recruited in a task-dependent manner during planning periods and execution periods of newly generated motor sequences. The observed differential bilateral activations (GENERATEPLAN N RECALLPLAN) are compatible with the cognitive aspects of a self-determined paradigm, as compared to our recent findings of lateralized activity in the anterior putamen during planning of automated motor sequences (Boecker et al., 2008) and highlight the role of the associative striatum for generating novel movement patterns. Our data also demonstrate a shift of activity from rostral to caudal regions of the basal ganglia at different stages of motor processing, from planning to execution. Acknowledgments We would like to acknowledge the work of our team of radiographers at the Department of Radiology for their technical assistance during fMRI scanning. Furthermore, we would like to thank all volunteers for participating in this study. This work was supported by grants from the BONFOR-Forschungskommission at the University Hospital Bonn.

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