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Compensatory cortical mechanisms in Parkinson's disease evidenced with fMRI during the performance of pre-learned sequential movements
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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s
Research Report
Compensatory cortical mechanisms in Parkinson's disease evidenced with fMRI during the performance of pre-learned sequential movements Rosella Mallol a , Alfonso Barrós-Loscertales b , Mario López a , Vicente Belloch c , Maria Antònia Parcet b , César Ávila b,⁎ a
Sección de Neurología. Hospital General de Castellón Castelló, Spain Dep. Psicología Bàsica, Clínica i Psicobiología. Universitat Jaume I, Castelló, Spain c Servicio de Radiología: ERESA, Valencia, Spain b
A R T I C LE I N FO
AB S T R A C T
Article history:
We used fMRI to study brain activity associated with the performance of a pre-learned
Accepted 4 February 2007
sequence of complex movements of the hand-made unimanually in a group of 13
Available online 27 February 2007
Parkinson's disease patients and a group of 11 control volunteers. Patients were scanned “off” medication. In controls, sequential movements led to the activation of bilateral
Keywords:
sensorimotor and premotor cortex, bilateral inferior parietal cortex, supplementary motor
Parkinson's disease
area, bilateral putamen and globus pallidus, and the left ventral lateral nucleus of the
Fronto-striatal motor circuit
thalamus. Sequential movements in the Parkinson's disease group were associated with a
Dopamine
similar pattern of activation, although relative decrease of activation in striatum and
Complex movement
thalamic areas was observed. Patients in comparison with controls showed a
fMRI
hyperactivation in ipsilateral premotor areas and a hypoactivation in structures of the
Compensatory mechanism
frontostriatal motor loop. Furthermore, patient scores in the motor scale of the UPDRS correlated positively with the activation thalamus and motor cortical areas during the sequential motor task. We concluded that in Parkinson's disease there is a compensatory mechanism of the dopamine deficit in frontostriatal motor circuits that increases participation in the execution of motor tasks of parietal–lateral premotor circuits. © 2007 Elsevier B.V. All rights reserved.
1.
Introduction
Parkinson's disease (PD) is characterized by a loss of dopamine projections to the striatum. The basal ganglia are integral components in a complex system of cortico-subcortical loops, and they are linked to cortical premotor and prefrontal areas via the ventral and dorsomedial thalamus (Alexander et al., 1986). At least five separate parallel loops have been proposed
to mediate motor behavior, eye movements and cognition. The motor circuit has been the subject of most investigations in PD. However, fMRI studies that investigate motor behavior have focused more on cortical brain structures rather than subcortical brain structures related to this circuitry. The basal ganglia are thought to mediate stimulus–response (S–R) learning, in which performance improves according to sensory feedback obtained as a result of a response. Evidence
⁎ Corresponding author. E-mail address: [email protected] (C. Ávila). 0006-8993/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2007.02.046
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for this has lead to the notion that basal ganglia are important for habit or skill learning (Packard and Knowlton, 2002) by selecting the appropriate movements/muscles to perform the task (Jueptner and Weiller, 1998). Animal research has amassed strong evidence that the striatum is necessary for both acquisition and expression of S–R associations. Neuroimaging studies in humans have also shown that activation of basal ganglia has been repeatedly found to accompany the acquisition, learning and consolidation of motor skill learning (Brashers-Krug et al., 1996; Karni et al., 1998; Hikosaka et al., 1999; Ungerleider et al., 2002). Importantly, activation of the caudate is more associated with the acquisition of new sequences in trial and error learning, whereas activation of the putamen is predominant during the execution of learned sequences (Miyachi et al., 1997; Nakamura et al., 1999). During the execution of a freely chosen unilateral motor task, activation was reduced in PD compared with normal subjects in the basal ganglia and the supplementary motor area (SMA), dorsolateral prefrontal cortex (DLPFC), and anterior cingulate that are, respectively, the main output projections of the basal ganglia to the motor, associative, and limbic loops (Jahanshahi et al., 1995; Playford et al., 1992). Conversely, the primary motor, parietal and lateral premotor cortices were normally activated. Consistently, apomorphine administration removed these differences between patients and controls (Jenkins et al., 1992). More recent studies have demonstrated a higher activation of a lateral cerebelloparieto-premotor circuit in PD compared to healthy subjects while activation was reduced in a mesial SMA-cingulate circuit (Rascol et al., 1997; Sabatini et al., 2000; Samuel et al., 1997). One of these studies also demonstrated that the reduction of SMA activation involves anterior SMA while its caudal part is more activated than in controls (Sabatini et al., 2000). Furthermore, the primary motor cortex, both ipsi- and contralateral to a motor task, may also be more activated in PD than in normal subjects, even at early stages of the disease (Sabatini et al., 2000; Thobois et al., 2000). We may hypothesize from this pattern of results of neuroimaging studies that in Parkinson's disease there is a switch from the use of striato-mesial frontal to parietal–lateral premotor circuits in order to facilitate the performance of complex finger and hand movements. Our objective in the present study is to investigate this pattern of results along with the use of fMRI by covering the whole brain. We specifically investigated brain areas involved in the performance of a learned and complex sequence of movements in both PD and control subjects to confirm the pattern of results reported by Sabatini et al. (2000). This study was carried out in a reduced group of patients using a liberal analysis and the basal ganglia were not scanned. Our interest for the present study is to replicate that study by improving these problems and using a more complex movement, such as hand rotation, to find a greater activation in frontostriatal areas. The specific hypotheses for this study were: (1) the striatum and the thalamus would be activated while performing the sequential motor task; (2) PD patients, especially those with more motor problems, would show a hypoactivation of these subcortical structures; and (3) these subcortical hypoactivations would be compensated by hyperactivating cortical brain areas, especially for those PD patients with more motor problems.
2.
Results
All participants performed the motor task with a similar frequency: means were 18.1 (SD = 1.37) and 17.8 (SD = 1.57) times per minute for control and patients, respectively. The differences were not significant (t(23) = 0. 40, p > 0.1). Table 1 shows brain areas activated during the execution of the motor task for both groups. Activation for controls was observed on SMA (proper and pre-SMA), bilateral precentral and postcentral gyrus, cerebellum, inferior parietal lobule, insula, globus pallidus, putamen and the ventral lateral nucleus of the thalamus (see Fig. 1). PD patients showed a similar pattern, but no significant activations of the putamen, the globus pallidus, the right insula and the left thalamus were observed. Finally, PD patients, unlike controls, showed a significant activation on the left inferior frontal gyrus (see Table 2 and Fig. 1). Comparisons between groups revealed that the control group showed greater activation in the thalamus, putamen, globus pallidus, insula, the pre-SMA and transverse temporal gyrus than PD patients (see Table 2 and Fig. 2). By contrast, PD patients showed greater activation than controls in the right lateral premotor cortex, the right parietal cortex, thalamus, posterior cingulate and the left middle temporal gyrus. We examined the relationship between scores on motor scale of the UPDRS and neural responses during the complex motor task using regression analyses. Motor scores correlated positively with activations in the right thalamus (k = 30; local maximum at x, y, z = 10, −7, 8, Z = 4.76, p < 0.001) and left pre-
Table 1 – Results of within-group analyses in control and patients during the motor task (p < 0001, uncorrected) Brain area
y
z
974 −34 −32 −34 556 6 −4 −4 93 −28 105 55 50 52 55 48 59 47 53 185 −51 −61 58 28 23 18
−29 −36 −46 −1 −7 4 −15 12 −5 −35 −37 −24 0 −41 −41 −48 −1
49 50 56 48 48 46 10 5 8 42 37 29 33 26 26 56 15
PD patients Left postcentral gyrus/middle frontal gyrus/ 2413 −40 precentral gyrus/SMA −24 −36 Right precentral gyrus/middle frontal gyrus 193 26 Right inferior parietal lobule 272 40 40 48
−25 −11 −17 −5 −46 −39 −31
44 54 51 54 52 39 38
Control group Left postcentral gyrus/inferior parietal lobule
SMA/Cingulate gyrus
Left putamen Right precentral gyrus Right inferior parietal lobule
Right precentral gyrus Left inferior parietal lobule Right superior parietal lobule Right putamen/globus pallidus
k
x
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Fig. 1 – Areas of brain activation during a complex motor task for the control group (up; red) and the PD group (down; blue).
motor cortex (k; = 87; local maximum at x, y, z = −44, 4, 47, Z = 4.48, p < 0.001). No significant negative correlations were found between motor scores and neural responses during the motor task (Fig. 3).
3.
Discussion
In healthy controls, our findings showed that the performance of the learned sequence of movements made with the right hand activated different brain areas of the frontostriatal motor circuit, including the left and right motor, premotor and parietal cortex, putamen, and globus pallidus. When compared with healthy controls, our findings revealed relatively decreased fMRI signals in the anterior SMA, thalamus, putamen, and globus pallidus, and relatively increased fMRI signals in the lateral premotor cortex and thalamus of PD patients performing learned sequential movements. These data were consistent with previously reported findings in SPECT, PET and fMRI (Playford et al., 1992; Sabatini et al., 2000;
Samuel et al., 1997), and they confirmed the compensatory mechanisms previously reported in PD patients that were based on a switch from the use of striato-mesial frontal to parietal–lateral premotor circuits to perform complex movements. As expected, regression analyses showed that these compensatory mechanisms in PD patients may be attributed to those patients with more motor problems as assessed by the ‘off’ medication scores of the Unified Parkinson's Disease Rating Scale motor part (UPDRS III). One important aspect of the present study is that the sequential motor task has significantly activated most of the structures involved in the frontostriatal motor circuit, including the primary motor cortex, the lateral and medial premotor cortex, putamen, globus pallidus and the ventral lateral nucleus of the thalamus. As the task was previously learned for 3 days, the activation of the caudate was not expected since the requirement of associative memory and conscious attention is not typically observed when the sequence has been learned (Jueptner and Weiller, 1998). Unfortunately, this task did not activate other structures such as subthalamic
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Table 2 – Results of between-group analyses: brain areas showing overactivity in controls rather than patients (up), and patients compared with controls during the motor task (bottom) (p < 0005, uncorrected) Brain area
k
x
y
z
Controls > PD patients Right thalamus 139 20 −18 −1 Right putamen 27 −1 −3 Right insula 128 40 −12 2 Anterior cingulate (BA24) 58 10 27 −3 Anterior cingulate (BA32) 33 −4 36 18 Left transverse temporal gyrus BA41 26 −40 −25 10 Precuneus 21 8 −74 44 Left lateral globus pallidus 28 −22 −18 −4 Right ventral anterior nucleus of the thalamus 26 16 −3 13 Pre-SMA 33 4 20 45 PD patients > Controls Right middle frontal gyrus BA6 Left posterior cingulate BA31 Right thalamus medial dorsal nucleus
142 35 47
38 2 40 −2 −45 32 6 −13 4
nucleus and substantia nigra. To a large extent therefore, we may consider that performing a practiced complex sequential motor task activates the motor circuit, plus other motor areas such as the cerebellum. Previous studies associated this activation of the striatum during pre-learned motor tasks with enhanced dopamine release in these areas (Goerendt et al., 2003). Between-group comparisons have revealed a pattern of results which is highly consistent with previous results. Patients with PD have shown a hypoactivation of structures that conformed to the frontostriatal motor circuit. Previous microdialysis and voltammetry studies have reported the involvement of DA in complex locomotor behavior (Trulson, 1985; Heyes et al., 1988; Hattori et al., 1994). Specifically, activation of nigral DA neurons has been shown during sequential
Fig. 3 – Positive brain correlates of scores on the motor scale of the UPDRS during the complex motor task. Activations were found in the right thalamus and the left premotor cortex. repetitive movement (Magarinos-Ascone et al., 1992). During the execution of movement sequences, DA has been suggested to facilitate temporal and spatial coding of the sequence (Cools, 1980). Then the depletion of dopamine within this circuit in PD patients would modify the normal functioning of the motor circuit, and may be responsible for the need of using other cortical or thalamic structures to perform the motor task. As differences in performance between groups were minor, presumably the use of other cortical areas in our PD group would act as a compensation mechanism. Regression analyses have shown that this compensatory mechanism is more evident in those patients with more motor problems. The results of the present study have shown that the performance of the pre-learned motor sequence has produced a hyperactivation of ipsilateral premotor and parietal cortex in patients with PD. A number of neuroimaging studies have provided evidence for a role of ipsilateral pathways in motor function, especially in complex motor tasks (Catalan et al., 1998; Kawashima et al., 1994). This activation was observed for both control and patient groups, but was stronger for patients. As typical ipsilateral motor activations have been observed in
Fig. 2 – Results obtained in the between-group comparisons: areas of relative overactivity in controls compared with patients with PD (red) and areas of relative overactivity of PD patients compared with controls (blue).
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patients with post-lesional motor deficits (Marque et al., 1997), we can infer that this activation may act as a compensatory mechanism to overcome the dysfunction of frontostriatal motor circuit. Contrary to a similar previous study (Sabatini et al., 2000), our data have not replicated the increase in fMRI signal in PD patients in SMA proper, contralateral premotor cortex and anterior cingulate when a sequential motor task was performed. Specifically, activation of SMA proper was a new and clear finding in that study and had not been previously observed in previous studies (Playford et al., 1992; Rascol et al., 1997; Samuel et al., 1997). Sabatini et al. (2000) attributed these new findings to differences in the sample or the task, although differences may also be attributed to a more liberal analysis of results and to the reduced sample used in that study. Future studies will serve to determine the role of SMA proper, contralateral premotor cortex, and the anterior cingulate in movement deficits observed in PD. The compensatory mechanisms described in this study are consistent with results obtained after different treatment strategies, since the pattern of hypoactivation in the PD group is reversed when treatments are administered. Surgical treatments such as pallidal stimulation induced an increased activation of the SMA and anterior cingulate (Fukuda et al., 2001), whereas the stimulation of subthalamic nucleus also increased activations of the rostral SMA, DLPFC, anterior cingulate, thalamus, and putamen (Ceballos-Baumann et al., 1999; Limousin et al., 1997; Strafella et al., 2003). In parallel with the restoration of normal activation, a reduction of the recruitment of compensatory pathways and in particular of the ipsilateral primary motor, lateral premotor, and parietal cortices has also been observed (Ceballos-Baumann et al., 1999; Limousin et al., 1997; Strafella et al., 2003). A similar simultaneous improvement of mesial premotor cortex activation and reductions in the lateral premotor cortical circuitry have been shown after levodopa challenge (Haslinger et al., 2001). Thus, the study of brain mechanisms involved in the movements of these patients may serve to find the best treatment strategy for each patient in the future. One interesting result in this study is that the right thalamus was also overactivated in the PD patients (especially those with more motor problems) to compensate the failure of the basal ganglia motor loop. A recent study also found an overactivation of the thalamus (and of the cerebellum) in PD patients when performing internally guided movements at the same frequency as controls (Cerasa et al., 2006). We did not study the cerebellum in this study, yet according to their results, we may interpret this overactivation of the thalamus as an increased recruitment of the cerebellar–thalamic pathway in PD patients to maintain the normal level of motor function. Our study has, however, some limitations. Firstly, the sample was relatively small (n = 13) and larger studies are required to replicate and expand on these results, which involved us having to apply a less stringent statistical threshold. Secondly, the analyses were not corrected for multiple comparisons since that kind of correction may be too restrictive for whole volume analysis, especially for the group comparison. Thirdly, although we studied all the key brain areas in PD, the scanner we used did not enable us to cover the entire brain, and we used a gap of 2 mm. Finally, the level of practice of the task may be different between subjects.
269
Although all the patients performed within the previously established limits (16–20 completed movements per minute), they may probably differ in the previous practice.
4.
Experimental procedure
4.1.
Participants
We studied 13 non-demented probable PD patients (54% men; mean age 64.91 ± 10.99 years) according to the criteria of Gibb and Lees (1988). The inclusion criteria were: age < 70 years; right-handed; and stages I–III of Hoehn and Yahr rated in on state. Mean score on the motor scale of the UPDRS scale before scanning (off medication) was 22.62 of a maximum of 56. The control group was formed by 11 healthy volunteer subjects (45% men; mean age 61.91 ± 8.45 years). Inclusion criteria were: age < 70 years; right-handed; lack of neurological or psychiatric antecedents. In addition to L-dopa (mean ± SD, 575 mg/day ± 311), 3 patients were on encatapone (600 mg/ day ± 0), 10 patients were on different dopaminergic agonists (pegolide, 3.38 mg/day ± 0.7, cabergoline 6 mg/day ± 0 and pramipexol; 2.1 mg/day ± 0), 7 were on selegilina (9.29 mg/ day ± 1.21) and 2 patients were on amantidine (200 mg/day).
4.2.
Motor task and procedure
Using a block design where epochs of activation were alternated with epochs of rest, all participants performed a complex sequential motor task consisting of 12 measurements. The task consisted of 4 opposition movements of each finger to the thumb and two consecutively rotation movements of the hand. Participants had to repeat the same series of movements during 30 s of data acquisition. During the rest block, participants were instructed not to move their hand nor any other part of their body. During the scanning, a number of overall movements were counted. All participants were instructed to practice the task at least 1 week before the fMRI scanning. The neurologist (M.L.) or the neuropsychologist (R.M.) showed the task and the rhythm to it. They evaluated whether the patient was able to conduct the task and instructed participants to do so for 15–30 min per day over the last 3 days. The objective was to perform the task at a frequency of 16–20 times per minute, and one relative was instructed to check that the patient fulfilled the task. The neurologist also explained to patients that they should withdraw the overnight intake of L-dopa, so all patients were scanned “off” medication. The scanning day participants were interrogated about the fulfillment of instructions, and performance was tested twice to verify that frequency was correct. All participants included in the study did the task at the same frequency, but the amplitude of movements was greater for controls than patients. Finally on the scanning day, patients completed the UPDRS scale in the “off” state.
4.3.
fMRI acquisition
Subjects were examined on a 1.5-T Signa CV (General Electric, Milwaukee, WI) using single-shot gradient-echo EPI sequence (TE = 50; TR = 3000; NEX = 1; FOV = 24 cm; matrix = 128 × 128;
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12 × 5 mm thick slices with 2 mm of interslice gap). The 12 slices were acquired in the axial plane parallel to the AC–PC line from bottom to top, providing a good coverage of the parietal, temporal, occipital, motor and premotor cortex without studying the cerebellum and the orbitofrontal cortex. A morphological volumetric sagittal 3D FSPGR (TR/TE 11/4,2; NEX = 1; FOV 24 × 24 cm; matrix = 256 × 256 × 124; 1.2 mm thick) was also acquired to superimpose statistical maps.
4.4.
Data analysis
Functional MRI images were processed using statistical parametric mapping (SPM2, Wellcome Department of Cognitive Neurology, London, UK). After discharging the first two volumes, functional scans of each individual were realigned to the first one for motion correction control. Subsequently, anatomical images were co-registered to the first functional scan, and all them normalized to MNI coordinates. Functional images were resampled every 2 mm using sinc interpolation during normalization, and smoothed with an 8-mm Gaussian kernel to decrease spatial noise. We transformed MNI coordinates to Talairach coordinates using a linear transformation and local maxima activations referred anatomically according to Talairach and Tournoux (1988). Statistical analysis was performed on individual and group data using the General Lineal Model as implemented in SPM2. Model estimation was convolved with hemodynamic response function (HRF) and a time derivative (1 s). Results from motion correction were included for each direction (translation and rotation) and modeled as regressors of noninterest in each subject. Low-frequency noise was removed with a high-pass filter (128 s) according to our block design. In a first level analysis, individual contrasts were defined from previous equal models across subjects. From these contrasts, an individual contrast image of parameter estimates was defined for a posterior second group analysis. Group analysis was performed using a random-effects model which allows a stronger generalization to the population. Thus, analyses were performed within and between groups. In order to study brain activations related to the complex motor task for each separate group, a one-sample t test (p < 0.001, uncorrected for multiple comparisons) was used. Group activations were compared using a two-sample t test (p < 0.005, uncorrected). A spatial threshold of 20 continuous active voxels was applied to avoid spike activations in each contrast. Regression analyses at the second level (p < 0.005, uncorrected) were computed within the patient group to explore whether individual differences in brain activation during the motor task covaried with the ‘off’ medication scores of the Unified Parkinson's Disease Rating Scale motor part (UPDRS III).
Acknowledgments This study was also supported by grant GV00-096-9 to César Ávila and grant PI021756 from the Spanish Ministry of Public Health to Maria Antònia Parcet. Alfonso Barrós received a research fellowship from the Generalitat Valenciana (Regional Government), Spain.
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Research Report
Compensatory cortical mechanisms in Parkinson's disease evidenced with fMRI during the performance of pre-learned sequential movements Rosella Mallol a , Alfonso Barrós-Loscertales b , Mario López a , Vicente Belloch c , Maria Antònia Parcet b , César Ávila b,⁎ a
Sección de Neurología. Hospital General de Castellón Castelló, Spain Dep. Psicología Bàsica, Clínica i Psicobiología. Universitat Jaume I, Castelló, Spain c Servicio de Radiología: ERESA, Valencia, Spain b
A R T I C LE I N FO
AB S T R A C T
Article history:
We used fMRI to study brain activity associated with the performance of a pre-learned
Accepted 4 February 2007
sequence of complex movements of the hand-made unimanually in a group of 13
Available online 27 February 2007
Parkinson's disease patients and a group of 11 control volunteers. Patients were scanned “off” medication. In controls, sequential movements led to the activation of bilateral
Keywords:
sensorimotor and premotor cortex, bilateral inferior parietal cortex, supplementary motor
Parkinson's disease
area, bilateral putamen and globus pallidus, and the left ventral lateral nucleus of the
Fronto-striatal motor circuit
thalamus. Sequential movements in the Parkinson's disease group were associated with a
Dopamine
similar pattern of activation, although relative decrease of activation in striatum and
Complex movement
thalamic areas was observed. Patients in comparison with controls showed a
fMRI
hyperactivation in ipsilateral premotor areas and a hypoactivation in structures of the
Compensatory mechanism
frontostriatal motor loop. Furthermore, patient scores in the motor scale of the UPDRS correlated positively with the activation thalamus and motor cortical areas during the sequential motor task. We concluded that in Parkinson's disease there is a compensatory mechanism of the dopamine deficit in frontostriatal motor circuits that increases participation in the execution of motor tasks of parietal–lateral premotor circuits. © 2007 Elsevier B.V. All rights reserved.
1.
Introduction
Parkinson's disease (PD) is characterized by a loss of dopamine projections to the striatum. The basal ganglia are integral components in a complex system of cortico-subcortical loops, and they are linked to cortical premotor and prefrontal areas via the ventral and dorsomedial thalamus (Alexander et al., 1986). At least five separate parallel loops have been proposed
to mediate motor behavior, eye movements and cognition. The motor circuit has been the subject of most investigations in PD. However, fMRI studies that investigate motor behavior have focused more on cortical brain structures rather than subcortical brain structures related to this circuitry. The basal ganglia are thought to mediate stimulus–response (S–R) learning, in which performance improves according to sensory feedback obtained as a result of a response. Evidence
⁎ Corresponding author. E-mail address: [email protected] (C. Ávila). 0006-8993/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2007.02.046
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for this has lead to the notion that basal ganglia are important for habit or skill learning (Packard and Knowlton, 2002) by selecting the appropriate movements/muscles to perform the task (Jueptner and Weiller, 1998). Animal research has amassed strong evidence that the striatum is necessary for both acquisition and expression of S–R associations. Neuroimaging studies in humans have also shown that activation of basal ganglia has been repeatedly found to accompany the acquisition, learning and consolidation of motor skill learning (Brashers-Krug et al., 1996; Karni et al., 1998; Hikosaka et al., 1999; Ungerleider et al., 2002). Importantly, activation of the caudate is more associated with the acquisition of new sequences in trial and error learning, whereas activation of the putamen is predominant during the execution of learned sequences (Miyachi et al., 1997; Nakamura et al., 1999). During the execution of a freely chosen unilateral motor task, activation was reduced in PD compared with normal subjects in the basal ganglia and the supplementary motor area (SMA), dorsolateral prefrontal cortex (DLPFC), and anterior cingulate that are, respectively, the main output projections of the basal ganglia to the motor, associative, and limbic loops (Jahanshahi et al., 1995; Playford et al., 1992). Conversely, the primary motor, parietal and lateral premotor cortices were normally activated. Consistently, apomorphine administration removed these differences between patients and controls (Jenkins et al., 1992). More recent studies have demonstrated a higher activation of a lateral cerebelloparieto-premotor circuit in PD compared to healthy subjects while activation was reduced in a mesial SMA-cingulate circuit (Rascol et al., 1997; Sabatini et al., 2000; Samuel et al., 1997). One of these studies also demonstrated that the reduction of SMA activation involves anterior SMA while its caudal part is more activated than in controls (Sabatini et al., 2000). Furthermore, the primary motor cortex, both ipsi- and contralateral to a motor task, may also be more activated in PD than in normal subjects, even at early stages of the disease (Sabatini et al., 2000; Thobois et al., 2000). We may hypothesize from this pattern of results of neuroimaging studies that in Parkinson's disease there is a switch from the use of striato-mesial frontal to parietal–lateral premotor circuits in order to facilitate the performance of complex finger and hand movements. Our objective in the present study is to investigate this pattern of results along with the use of fMRI by covering the whole brain. We specifically investigated brain areas involved in the performance of a learned and complex sequence of movements in both PD and control subjects to confirm the pattern of results reported by Sabatini et al. (2000). This study was carried out in a reduced group of patients using a liberal analysis and the basal ganglia were not scanned. Our interest for the present study is to replicate that study by improving these problems and using a more complex movement, such as hand rotation, to find a greater activation in frontostriatal areas. The specific hypotheses for this study were: (1) the striatum and the thalamus would be activated while performing the sequential motor task; (2) PD patients, especially those with more motor problems, would show a hypoactivation of these subcortical structures; and (3) these subcortical hypoactivations would be compensated by hyperactivating cortical brain areas, especially for those PD patients with more motor problems.
2.
Results
All participants performed the motor task with a similar frequency: means were 18.1 (SD = 1.37) and 17.8 (SD = 1.57) times per minute for control and patients, respectively. The differences were not significant (t(23) = 0. 40, p > 0.1). Table 1 shows brain areas activated during the execution of the motor task for both groups. Activation for controls was observed on SMA (proper and pre-SMA), bilateral precentral and postcentral gyrus, cerebellum, inferior parietal lobule, insula, globus pallidus, putamen and the ventral lateral nucleus of the thalamus (see Fig. 1). PD patients showed a similar pattern, but no significant activations of the putamen, the globus pallidus, the right insula and the left thalamus were observed. Finally, PD patients, unlike controls, showed a significant activation on the left inferior frontal gyrus (see Table 2 and Fig. 1). Comparisons between groups revealed that the control group showed greater activation in the thalamus, putamen, globus pallidus, insula, the pre-SMA and transverse temporal gyrus than PD patients (see Table 2 and Fig. 2). By contrast, PD patients showed greater activation than controls in the right lateral premotor cortex, the right parietal cortex, thalamus, posterior cingulate and the left middle temporal gyrus. We examined the relationship between scores on motor scale of the UPDRS and neural responses during the complex motor task using regression analyses. Motor scores correlated positively with activations in the right thalamus (k = 30; local maximum at x, y, z = 10, −7, 8, Z = 4.76, p < 0.001) and left pre-
Table 1 – Results of within-group analyses in control and patients during the motor task (p < 0001, uncorrected) Brain area
y
z
974 −34 −32 −34 556 6 −4 −4 93 −28 105 55 50 52 55 48 59 47 53 185 −51 −61 58 28 23 18
−29 −36 −46 −1 −7 4 −15 12 −5 −35 −37 −24 0 −41 −41 −48 −1
49 50 56 48 48 46 10 5 8 42 37 29 33 26 26 56 15
PD patients Left postcentral gyrus/middle frontal gyrus/ 2413 −40 precentral gyrus/SMA −24 −36 Right precentral gyrus/middle frontal gyrus 193 26 Right inferior parietal lobule 272 40 40 48
−25 −11 −17 −5 −46 −39 −31
44 54 51 54 52 39 38
Control group Left postcentral gyrus/inferior parietal lobule
SMA/Cingulate gyrus
Left putamen Right precentral gyrus Right inferior parietal lobule
Right precentral gyrus Left inferior parietal lobule Right superior parietal lobule Right putamen/globus pallidus
k
x
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Fig. 1 – Areas of brain activation during a complex motor task for the control group (up; red) and the PD group (down; blue).
motor cortex (k; = 87; local maximum at x, y, z = −44, 4, 47, Z = 4.48, p < 0.001). No significant negative correlations were found between motor scores and neural responses during the motor task (Fig. 3).
3.
Discussion
In healthy controls, our findings showed that the performance of the learned sequence of movements made with the right hand activated different brain areas of the frontostriatal motor circuit, including the left and right motor, premotor and parietal cortex, putamen, and globus pallidus. When compared with healthy controls, our findings revealed relatively decreased fMRI signals in the anterior SMA, thalamus, putamen, and globus pallidus, and relatively increased fMRI signals in the lateral premotor cortex and thalamus of PD patients performing learned sequential movements. These data were consistent with previously reported findings in SPECT, PET and fMRI (Playford et al., 1992; Sabatini et al., 2000;
Samuel et al., 1997), and they confirmed the compensatory mechanisms previously reported in PD patients that were based on a switch from the use of striato-mesial frontal to parietal–lateral premotor circuits to perform complex movements. As expected, regression analyses showed that these compensatory mechanisms in PD patients may be attributed to those patients with more motor problems as assessed by the ‘off’ medication scores of the Unified Parkinson's Disease Rating Scale motor part (UPDRS III). One important aspect of the present study is that the sequential motor task has significantly activated most of the structures involved in the frontostriatal motor circuit, including the primary motor cortex, the lateral and medial premotor cortex, putamen, globus pallidus and the ventral lateral nucleus of the thalamus. As the task was previously learned for 3 days, the activation of the caudate was not expected since the requirement of associative memory and conscious attention is not typically observed when the sequence has been learned (Jueptner and Weiller, 1998). Unfortunately, this task did not activate other structures such as subthalamic
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Table 2 – Results of between-group analyses: brain areas showing overactivity in controls rather than patients (up), and patients compared with controls during the motor task (bottom) (p < 0005, uncorrected) Brain area
k
x
y
z
Controls > PD patients Right thalamus 139 20 −18 −1 Right putamen 27 −1 −3 Right insula 128 40 −12 2 Anterior cingulate (BA24) 58 10 27 −3 Anterior cingulate (BA32) 33 −4 36 18 Left transverse temporal gyrus BA41 26 −40 −25 10 Precuneus 21 8 −74 44 Left lateral globus pallidus 28 −22 −18 −4 Right ventral anterior nucleus of the thalamus 26 16 −3 13 Pre-SMA 33 4 20 45 PD patients > Controls Right middle frontal gyrus BA6 Left posterior cingulate BA31 Right thalamus medial dorsal nucleus
142 35 47
38 2 40 −2 −45 32 6 −13 4
nucleus and substantia nigra. To a large extent therefore, we may consider that performing a practiced complex sequential motor task activates the motor circuit, plus other motor areas such as the cerebellum. Previous studies associated this activation of the striatum during pre-learned motor tasks with enhanced dopamine release in these areas (Goerendt et al., 2003). Between-group comparisons have revealed a pattern of results which is highly consistent with previous results. Patients with PD have shown a hypoactivation of structures that conformed to the frontostriatal motor circuit. Previous microdialysis and voltammetry studies have reported the involvement of DA in complex locomotor behavior (Trulson, 1985; Heyes et al., 1988; Hattori et al., 1994). Specifically, activation of nigral DA neurons has been shown during sequential
Fig. 3 – Positive brain correlates of scores on the motor scale of the UPDRS during the complex motor task. Activations were found in the right thalamus and the left premotor cortex. repetitive movement (Magarinos-Ascone et al., 1992). During the execution of movement sequences, DA has been suggested to facilitate temporal and spatial coding of the sequence (Cools, 1980). Then the depletion of dopamine within this circuit in PD patients would modify the normal functioning of the motor circuit, and may be responsible for the need of using other cortical or thalamic structures to perform the motor task. As differences in performance between groups were minor, presumably the use of other cortical areas in our PD group would act as a compensation mechanism. Regression analyses have shown that this compensatory mechanism is more evident in those patients with more motor problems. The results of the present study have shown that the performance of the pre-learned motor sequence has produced a hyperactivation of ipsilateral premotor and parietal cortex in patients with PD. A number of neuroimaging studies have provided evidence for a role of ipsilateral pathways in motor function, especially in complex motor tasks (Catalan et al., 1998; Kawashima et al., 1994). This activation was observed for both control and patient groups, but was stronger for patients. As typical ipsilateral motor activations have been observed in
Fig. 2 – Results obtained in the between-group comparisons: areas of relative overactivity in controls compared with patients with PD (red) and areas of relative overactivity of PD patients compared with controls (blue).
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patients with post-lesional motor deficits (Marque et al., 1997), we can infer that this activation may act as a compensatory mechanism to overcome the dysfunction of frontostriatal motor circuit. Contrary to a similar previous study (Sabatini et al., 2000), our data have not replicated the increase in fMRI signal in PD patients in SMA proper, contralateral premotor cortex and anterior cingulate when a sequential motor task was performed. Specifically, activation of SMA proper was a new and clear finding in that study and had not been previously observed in previous studies (Playford et al., 1992; Rascol et al., 1997; Samuel et al., 1997). Sabatini et al. (2000) attributed these new findings to differences in the sample or the task, although differences may also be attributed to a more liberal analysis of results and to the reduced sample used in that study. Future studies will serve to determine the role of SMA proper, contralateral premotor cortex, and the anterior cingulate in movement deficits observed in PD. The compensatory mechanisms described in this study are consistent with results obtained after different treatment strategies, since the pattern of hypoactivation in the PD group is reversed when treatments are administered. Surgical treatments such as pallidal stimulation induced an increased activation of the SMA and anterior cingulate (Fukuda et al., 2001), whereas the stimulation of subthalamic nucleus also increased activations of the rostral SMA, DLPFC, anterior cingulate, thalamus, and putamen (Ceballos-Baumann et al., 1999; Limousin et al., 1997; Strafella et al., 2003). In parallel with the restoration of normal activation, a reduction of the recruitment of compensatory pathways and in particular of the ipsilateral primary motor, lateral premotor, and parietal cortices has also been observed (Ceballos-Baumann et al., 1999; Limousin et al., 1997; Strafella et al., 2003). A similar simultaneous improvement of mesial premotor cortex activation and reductions in the lateral premotor cortical circuitry have been shown after levodopa challenge (Haslinger et al., 2001). Thus, the study of brain mechanisms involved in the movements of these patients may serve to find the best treatment strategy for each patient in the future. One interesting result in this study is that the right thalamus was also overactivated in the PD patients (especially those with more motor problems) to compensate the failure of the basal ganglia motor loop. A recent study also found an overactivation of the thalamus (and of the cerebellum) in PD patients when performing internally guided movements at the same frequency as controls (Cerasa et al., 2006). We did not study the cerebellum in this study, yet according to their results, we may interpret this overactivation of the thalamus as an increased recruitment of the cerebellar–thalamic pathway in PD patients to maintain the normal level of motor function. Our study has, however, some limitations. Firstly, the sample was relatively small (n = 13) and larger studies are required to replicate and expand on these results, which involved us having to apply a less stringent statistical threshold. Secondly, the analyses were not corrected for multiple comparisons since that kind of correction may be too restrictive for whole volume analysis, especially for the group comparison. Thirdly, although we studied all the key brain areas in PD, the scanner we used did not enable us to cover the entire brain, and we used a gap of 2 mm. Finally, the level of practice of the task may be different between subjects.
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Although all the patients performed within the previously established limits (16–20 completed movements per minute), they may probably differ in the previous practice.
4.
Experimental procedure
4.1.
Participants
We studied 13 non-demented probable PD patients (54% men; mean age 64.91 ± 10.99 years) according to the criteria of Gibb and Lees (1988). The inclusion criteria were: age < 70 years; right-handed; and stages I–III of Hoehn and Yahr rated in on state. Mean score on the motor scale of the UPDRS scale before scanning (off medication) was 22.62 of a maximum of 56. The control group was formed by 11 healthy volunteer subjects (45% men; mean age 61.91 ± 8.45 years). Inclusion criteria were: age < 70 years; right-handed; lack of neurological or psychiatric antecedents. In addition to L-dopa (mean ± SD, 575 mg/day ± 311), 3 patients were on encatapone (600 mg/ day ± 0), 10 patients were on different dopaminergic agonists (pegolide, 3.38 mg/day ± 0.7, cabergoline 6 mg/day ± 0 and pramipexol; 2.1 mg/day ± 0), 7 were on selegilina (9.29 mg/ day ± 1.21) and 2 patients were on amantidine (200 mg/day).
4.2.
Motor task and procedure
Using a block design where epochs of activation were alternated with epochs of rest, all participants performed a complex sequential motor task consisting of 12 measurements. The task consisted of 4 opposition movements of each finger to the thumb and two consecutively rotation movements of the hand. Participants had to repeat the same series of movements during 30 s of data acquisition. During the rest block, participants were instructed not to move their hand nor any other part of their body. During the scanning, a number of overall movements were counted. All participants were instructed to practice the task at least 1 week before the fMRI scanning. The neurologist (M.L.) or the neuropsychologist (R.M.) showed the task and the rhythm to it. They evaluated whether the patient was able to conduct the task and instructed participants to do so for 15–30 min per day over the last 3 days. The objective was to perform the task at a frequency of 16–20 times per minute, and one relative was instructed to check that the patient fulfilled the task. The neurologist also explained to patients that they should withdraw the overnight intake of L-dopa, so all patients were scanned “off” medication. The scanning day participants were interrogated about the fulfillment of instructions, and performance was tested twice to verify that frequency was correct. All participants included in the study did the task at the same frequency, but the amplitude of movements was greater for controls than patients. Finally on the scanning day, patients completed the UPDRS scale in the “off” state.
4.3.
fMRI acquisition
Subjects were examined on a 1.5-T Signa CV (General Electric, Milwaukee, WI) using single-shot gradient-echo EPI sequence (TE = 50; TR = 3000; NEX = 1; FOV = 24 cm; matrix = 128 × 128;
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12 × 5 mm thick slices with 2 mm of interslice gap). The 12 slices were acquired in the axial plane parallel to the AC–PC line from bottom to top, providing a good coverage of the parietal, temporal, occipital, motor and premotor cortex without studying the cerebellum and the orbitofrontal cortex. A morphological volumetric sagittal 3D FSPGR (TR/TE 11/4,2; NEX = 1; FOV 24 × 24 cm; matrix = 256 × 256 × 124; 1.2 mm thick) was also acquired to superimpose statistical maps.
4.4.
Data analysis
Functional MRI images were processed using statistical parametric mapping (SPM2, Wellcome Department of Cognitive Neurology, London, UK). After discharging the first two volumes, functional scans of each individual were realigned to the first one for motion correction control. Subsequently, anatomical images were co-registered to the first functional scan, and all them normalized to MNI coordinates. Functional images were resampled every 2 mm using sinc interpolation during normalization, and smoothed with an 8-mm Gaussian kernel to decrease spatial noise. We transformed MNI coordinates to Talairach coordinates using a linear transformation and local maxima activations referred anatomically according to Talairach and Tournoux (1988). Statistical analysis was performed on individual and group data using the General Lineal Model as implemented in SPM2. Model estimation was convolved with hemodynamic response function (HRF) and a time derivative (1 s). Results from motion correction were included for each direction (translation and rotation) and modeled as regressors of noninterest in each subject. Low-frequency noise was removed with a high-pass filter (128 s) according to our block design. In a first level analysis, individual contrasts were defined from previous equal models across subjects. From these contrasts, an individual contrast image of parameter estimates was defined for a posterior second group analysis. Group analysis was performed using a random-effects model which allows a stronger generalization to the population. Thus, analyses were performed within and between groups. In order to study brain activations related to the complex motor task for each separate group, a one-sample t test (p < 0.001, uncorrected for multiple comparisons) was used. Group activations were compared using a two-sample t test (p < 0.005, uncorrected). A spatial threshold of 20 continuous active voxels was applied to avoid spike activations in each contrast. Regression analyses at the second level (p < 0.005, uncorrected) were computed within the patient group to explore whether individual differences in brain activation during the motor task covaried with the ‘off’ medication scores of the Unified Parkinson's Disease Rating Scale motor part (UPDRS III).
Acknowledgments This study was also supported by grant GV00-096-9 to César Ávila and grant PI021756 from the Spanish Ministry of Public Health to Maria Antònia Parcet. Alfonso Barrós received a research fellowship from the Generalitat Valenciana (Regional Government), Spain.
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