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Nigrostriatal dopamine system and motor lateralization
Behavioural Brain Research 112 (2000) 63 – 68 www.elsevier.com/locate/bbr
Research report
Nigrostriatal dopamine system and motor lateralization Rau´l de la Fuente-Ferna´ndez, Asha Kishore, Donald B. Calne, Thomas J. Ruth, A. Jon Stoessl * Neurodegenerati6e Disorders Centre, Vancou6er Hospital and Health Sciences Centre, Uni6ersity of British Columbia, Purdy Pa6ilion, 2221 Wesbrook Mall, Vancou6er, BC, Canada V6T 2B5 Received 2 December 1999; received in revised form 25 January 2000; accepted 1 February 2000
Abstract The mechanism by which most people favor use of the right hand remains unknown. It has been proposed that asymmetries in the nigrostriatal dopamine system may be related to motor lateralization in humans. We explored this hypothesis in vivo by using [18F]fluorodopa positron emission tomography. Whereas the degree of right hand preference was found to correlate with left putamen dominance as assessed by asymmetry in fluorodopa uptake (Ki ), right caudate dominance was positively correlated with the level of performance during simultaneous bimanual movements in right-handed normal subjects. In addition, right-handed patients with Parkinson’s disease with higher right than left caudate Ki performed much better in bimanual movement tests than those in whom the Ki value of the left caudate was higher than that of the right. These findings support the notion that the nigrostriatal dopaminergic system may play a role in motor lateralization, and suggest a functional model for bimanual movements. We propose that the skill for performing simultaneous bilateral hand movements in right-handed subjects might depend upon both the activation (through the dominant left putamen circuitry) of the left supplementary motor area (SMA), and the inhibition (through the right caudate circuitry) of motor programs stored in the right SMA. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Handedness; Fluorodopa; Positron emission tomography; Putamen; Caudate nucleus; Supplementary motor area; Dorsolateral prefrontal cortex; Parkinson’s disease
1. Introduction Most people favor use of the right hand for performing tasks. This right motor lateralization is thought to be related, at least partly, to higher cerebral functions, particularly language representation areas on the left brain hemisphere [15]. Although handedness could have a genetic basis, studies of heritability have provided no definite result [12,27]. Other factors may, therefore, influence handedness [16]. It is noteworthy that animals also show forelimb preference [17,22,39]. It has long been proposed that asymmetries of the nigrostriatal dopamine system are related to asym-
* Corresponding author. Tel.: +1-604-8227935; fax: + 1-6048227866. E-mail address: [email protected] (A.J. Stoessl)
metries in motor preference. Thus, there seem to be small differences between left and right striatal dopamine levels that could reflect spatial preferences in rats [17,39]. In humans, conflicting results have been reported, but there do seem to be higher amounts of dopamine in the left globus pallidus than in the right [18,32]. In addition, the size of the left globus pallidus has been found to be larger than the right [25]. However, the main target of the nigrostriatal dopamine system is not the globus pallidus but the striatum (caudate and putamen) [1–4,14,21]. To date, no definite nigrostriatal asymmetries have been linked to handedness. Handedness may be a graded characteristic and, therefore, both qualitative and quantitative data on hand preference are needed to evaluate whether asymmetries in the nigrostriatal dopamine system relate to motor lateralization. Furthermore, the caudate and
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R. de la Fuente-Ferna´ndez et al. / Beha6ioural Brain Research 112 (2000) 63–68
putamen are likely to have different functions. There is good evidence that the putamen is predominantly involved in motor execution; the caudate nucleus, on the other hand, seems to play a role in motor planning and motor learning [1– 4,14,21]. We hypothesized that whereas hand preference would be related to side-toside asymmetries in putamen dopaminergic activity, asymmetries in caudate dopaminergic activity might correlate with the performance of complex movements (e.g. bimanual movements). To explore these hypotheses we examined in vivo the nigrostriatal dopamine system using fluorine-18-6-fluorodopa (FD) positron emission tomography (PET). Several studies have shown that FD PET is a reliable [38] and useful tool for exploring the nigrostriatal dopaminergic projection [34]. The FD uptake rate constant (Ki ), which represents the trapping of FD in the nigrostriatal terminals, is highly correlated with striatal dopamine levels [34]. It is not clear if left-handedness represents a situation opposite to that seen in right-handers, or simply a loss of the usual brain asymmetry. Anatomical and functional studies have shown that the degree of brain asymmetry is much less striking in left-handers compared to right-handers [15,23]. The situation in individuals with no clear hand preference (ambidextrous) could be even more complex. Therefore, we focused our study on individuals with a clear right hand preference [29]. The degree of motor lateralization and ability to perform simultaneous bimanual movements were measured by using the Purdue pegboard test (PPBT) [36]. Left –right asymmetries in caudate and putamen Ki values, and asymmetries in right – left PPBT were calculated using normalized values. We expected to find left putamen dominance on unilateral PPBT, and left caudate dominance on bilateral PPBT.
2. Materials and methods
2.1. Subject selection We studied 20 right-handed normal volunteers. There were nine men and 11 women, aged 479 17 years (mean 9SD). All normal subjects reported right-hand preference in everyday activities [29], and the neurological examination was entirely normal in all of them. We also studied 19 right-handed patients with asymmetric Parkinson’s disease (PD). All patients satisfied the clinical criteria for definite PD [11]. In the patient group there were 12 men and seven women, aged 56 9 9.7 years (mean9 SD). All patients were evaluated between 08:00 and 10:00 h after at least 12 h of withdrawal of medications. The severity of parkinsonism was evaluated using the Modified Columbia Scale (MCS) score [13] and the PPBT [36]. Parkinsonism was defined as asymmetric when the difference between the right and
left MCS score was of more than 1 point, and there was at least 1 point difference between right and left PPBT. All clinical assessments (including the PPBT) were performed prior to the PET scans.
2.2. PPBT The PPBT [36] records the number of pegs inserted into a pegboard in 30 s unilaterally with each hand separately and bilaterally with both hands simultaneously. An experienced technician performed the test. We chose the PPBT to assess the degree of motor lateralization because this test has been found to correlate with striatal Ki in PD [37].
2.3. FD PET All PET studies were performed using an ECAT 953B/31 tomogragh in 2D mode. The details of the protocol have been described elsewhere [38]. The subject was positioned with the image plane parallel to the orbito-meatal line. A thermo-plastic face mask was molded to restrain head movement. Tissue attenuation was measured for later use in attenuation correction. Subjects received an injection of 5 mCi of FD 1 h after premedication with 150–200 mg of carbidopa. Twelve sequential emission scans, each lasting 10 min, were performed starting at the midpoint of the FD injection. Activity collected from 60 to 120 min after FD administration was summed to produce an integral image. On this image regions of interest (ROIs) were placed. A small circular ROI (diameter 8.8 mm) was positioned by inspection on each caudate nucleus and three circular ROIs (diameter 8.8 mm) were place without overlap along the axis of each putamen. The ROIs were adjusted on the integral image to maximize the average ROI activity. Three background circular ROIs (diameter 19.4 mm) were placed on the parieto-occipital cortex. This was repeated for the five slices where the caudate and putamen were most clearly seen, and replicated over 12 time frames. The tissue data were analyzed by the graphical method described by Patlak and Blasberg [31] on the values from 20 to 120 min using the cortical input function [10]. FD uptake rate constants (Ki ) were calculated for the right and left caudate and putamen. Subjects gave written informed consent. The study was authorized by the UBC Ethics Committee.
2.4. Statistical analysis Normalized left–right differences for caudate and putamen Ki were calculated using the formula: (left− right)/(1/2 × (left+ right)). Similarly, normalized right– left asymmetries in PPBT hand performance were calculated by the formula: (right−left)/(1/2 ×(right+
R. de la Fuente-Ferna´ndez et al. / Beha6ioural Brain Research 112 (2000) 63–68
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left)), which gives an objective estimate of the degree of right hand preference. Four correlation analyses were decided in advance: correlation of right – left PPBT asymmetry with left– right asymmetries in putamen and caudate Ki, and correlation of bilateral PPBT score with left–right asymmetries in caudate and putamen Ki. Parametric and non-parametric statistical methods were used as appropriate; two-tailed P-values B0.05 were considered as statistically significant. 3. Results
3.1. Normal 6olunteers There were no left – right differences (paired t-test) for caudate Ki (mean9 SD, 0.00959 0.001 versus 0.00909 0.001, P = 0.16) or putamen Ki (mean 9 SD, 0.008090.001 versus 0.0080 90.001, P =0.93). Females and males had similar Ki values for both caudate and putamen (Table 1). Table 1 Values (mean 9 SD) of [18F]fluorodopa uptake constant (Ki ) (ml·min−1·cc−1) in right-handed normal volunteersa Right caudate
Left caudate
Right putamen
Left putamen
Male
0.0088 90.001
0.0092 90.001
0.0079 9 0.001
0.0080 90.001
Female
0.0092 90.001
0.0097 90.001
0.0081 9 0.002
0.0080 9 0.001
a
t-Test, P\0.2 for all comparisons.
Fig. 1. Degree of right hand preference as estimated by unilateral PPBT (see Section 2) plotted against left–right putamen Ki asymmetry in right-handed normal subjects (horizontal axis, values to the right and left of the zero score represent left and right putamen dominance, respectively). A significant correlation was observed (Spearman rank correlation coefficient: r = 0.64, P= 0.0026). Caudate Ki asymmetry did not correlate with right hand preference (Spearman rank correlation coefficient: r= 0.014, P= 0.95).
Fig. 2. Simultaneous bimanual movements (bilateral PPBT score) plotted against left – right caudate Ki asymmetry for right-handed normal subjects (a) and right-handed patients with Parkinson’s disease (b). Again, values to the right and left of the zero score of the horizontal axis represent left and right caudate dominance, respectively. Regression analysis showed a significant inverse correlation in both cases (for normal subjects: r = −0.76, P=0.00010; for patients: r = −0.60, P=0.0066). In normal subjects, putamen Ki asymmetry did not correlate with bilateral PPBT score (r =0.33, P =0.15).
As expected, we observed that asymmetries in right– left PPBT correlated positively with left–right asymmetries in putamen Ki (Spearman rank correlation coefficient: r= 0.64, P= 0.0026) (Fig. 1). No such correlation was found for caudate (Spearman rank correlation coefficient: r= 0.014, P= 0.95). We also found that, whereas left–right putamen Ki asymmetry did not correlate with simultaneous bilateral hand performance (bilateral PPBT) (r=0.33, P= 0.15), caudate Ki asymmetry correlated negatively with bimanual movements (r= − 0.76, P= 0.00010) (Fig. 2a). In other words, contrary to our prediction, our results suggest that is the right caudate, and not the left, that plays a dominant role in motor control in right-handed subjects.
3.2. Patients with PD To evaluate further the role of the caudate nucleus in bimanual movement performance, we next studied patients with PD. PD is characterized by extensive dam-
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age to the nigrostriatal dopamine system, the putamen being considerably more affected by dopamine deficiency than the caudate nucleus [8,24]. In addition to difficulty in performing simple movements, PD patients have more difficulty when they attempt to execute bilateral coordinated movements [6,7]. The occurrence of asymmetric motor signs is an almost constant feature of PD [26]. Therefore, the study of PD offers an opportunity to explore whether the caudate nucleus plays a crucial role in bimanual movements. Based on our findings in normal subjects we expected to find a greater bilateral PPBT score in patients with higher right than left caudate Ki (adjusting for differences in disease severity, irrespective of which body side is clinically more affected). Twelve patients showed right-predominant parkinsonism, and seven left-predominant parkinsonism. In all cases the most affected body side had also been the side in which symptoms had started. Regression analysis showed that caudate Ki asymmetry correlated negatively with bilateral PPBT score both before (r= − 0.60, P =0.0066) (Fig. 2b), and after adjusting for severity of parkinsonism (including in the regression model either total striatum Ki (P = 0.0043) or MCS score (P=0.026) as variables measuring overall severity of parkinsonism). As predicted, patients with higher right than left caudate Ki (n = 12) were found to perform much better in bilateral PPBT than those in whom the Ki value of the left caudate was higher than that of the right (n= 7) (mean9SD, 18.4293.82 versus 11.14 94.85; independent-samples t-test value = 3.63, P=0.0021). This difference remained significant after adjusting for between group differences in severity of parkinsonism by analysis of covariance (ANCOVA) (using either total striatum Ki (P = 0.0038) or MCS score (P=0.0033) as covariates).
4. Discussion This study provides in vivo evidence suggesting that asymmetries in the nigrostriatal dopaminergic system may play a role in motor lateralization in humans. Because the striatal FD uptake constant (Ki ) correlates highly with striatal dopamine levels [34], we can use the Ki values as a good estimate for the underlying levels of dopamine. We found that the degree of right hand preference, as estimated objectively by the PPBT, increased with left putamen dopaminergic dominance in right-handed subjects. This suggests that in righthanded subjects, the levels of dopamine are higher in the left putamen than in the right. Similarly, previous post mortem studies have reported left-biased levels of dopamine in the lateral globus pallidus [18]. However, we did not find a significant difference in mean Ki values between the left and right sides, suggesting that
the effect is graded rather than absolute. Furthermore, our results suggest that brain lateralization related to handedness may be more complex than expected. Indeed, it was the right caudate, not the left, that was found to play a dominant role in controlling simultaneous bimanual movements. As previously noted by others [28] the degree of handedness may be taskcontingent. Current available data allow us to integrate our findings in a model. It is thought that the supplementary motor area (SMA), which receives input from the putamen [1–4,14,21], is involved in motor programming [20,30,35]. The caudate nucleus, on the other hand, receives input from, and projects (via the globus pallidus and thalamus) back to the dorsolateral prefrontal cortex [1–4,14,21]. Although the function of the dorsolateral prefrontal cortex remains obscure, it is known that this cortical region is connected with the SMA [5]. According to current models the basal ganglia circuitry acts to modulate the excitatory thalamocortical output. We propose that the skill for performing simultaneous bilateral hand movements in right-handed subjects might depend upon the activation (through the dominant left putamen–globus pallidus–thalamocortical loop) of motor programs stored in the left SMA, while motor programs stored in the right SMA are suppressed by the right-caudate dependent projection from the dorsolateral prefrontal cortex. In other words, whereas the net effect of stimulating putaminal dopamine receptors would be excitation of the motor cortex, stimulating dopamine receptors in the caudate nucleus would lead to inhibition. Several clinical observations support this hypothesis. Thus, whereas lesions in putamen are associated with contralateral loss of motor function [9], caudate lesions lead to contralateral spontaneous abnormal movements (hyperkinesia, dyskinesia, chorea) or generalized motor hyperactivity [9]. In PD, dopamine depletion is much more severe in the putamen than in the caudate, and so loss of movement (akinesia, bradykinesia) occurs. It is relevant that in patients with PD studies of cerebral blood flow reveal reduced activation of the SMA, which is associated with relative overactivity in lateral premotor regions [33]. After partial restoration of the nigrostriatal dopaminergic transmission by levodopa treatment, many PD patients experience dyskinesias. It is not clear whether the caudate-dependent circuitry plays a major role in the pathogenesis of drug-induced dyskinesias. We have no research methods to address the question of cause versus effect. The asymmetric indices of dopaminergic brain function that we report here could play a causal role in determining handedness, but they could, equally, be the result of long term asymmetric use. Nevertheless, our study does provide some evidence supporting the existence of a cause–effect link. Thus, although (due to the damage to the nigrostriatal
R. de la Fuente-Ferna´ndez et al. / Beha6ioural Brain Research 112 (2000) 63–68
dopaminergic system that occurs in PD) motor performance was worse in patients with PD than in normal subjects, similar correlations between caudate Ki asymmetry and bilateral PPBT were found in both groups of subjects. Finally, we recognize that by using PPBT we analyzed essentially self-paced freely chosen movements. Hence, the basal ganglia functional model proposed here may not apply to other types of movements [19,28].
Acknowledgements This work was funded by the National Parkinson Foundation (Miami), the Medical Research Council of Canada, the Parkinson Foundation of Canada, and the Pacific Parkinson Research Institute (Vancouver, BC, Canada). R. de la Fuente-Ferna´ndez was supported in part by a grant from the Xunta de Galicia, Spain. We are grateful to the members of the UBC/TRIUMF PET team.
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Research report
Nigrostriatal dopamine system and motor lateralization Rau´l de la Fuente-Ferna´ndez, Asha Kishore, Donald B. Calne, Thomas J. Ruth, A. Jon Stoessl * Neurodegenerati6e Disorders Centre, Vancou6er Hospital and Health Sciences Centre, Uni6ersity of British Columbia, Purdy Pa6ilion, 2221 Wesbrook Mall, Vancou6er, BC, Canada V6T 2B5 Received 2 December 1999; received in revised form 25 January 2000; accepted 1 February 2000
Abstract The mechanism by which most people favor use of the right hand remains unknown. It has been proposed that asymmetries in the nigrostriatal dopamine system may be related to motor lateralization in humans. We explored this hypothesis in vivo by using [18F]fluorodopa positron emission tomography. Whereas the degree of right hand preference was found to correlate with left putamen dominance as assessed by asymmetry in fluorodopa uptake (Ki ), right caudate dominance was positively correlated with the level of performance during simultaneous bimanual movements in right-handed normal subjects. In addition, right-handed patients with Parkinson’s disease with higher right than left caudate Ki performed much better in bimanual movement tests than those in whom the Ki value of the left caudate was higher than that of the right. These findings support the notion that the nigrostriatal dopaminergic system may play a role in motor lateralization, and suggest a functional model for bimanual movements. We propose that the skill for performing simultaneous bilateral hand movements in right-handed subjects might depend upon both the activation (through the dominant left putamen circuitry) of the left supplementary motor area (SMA), and the inhibition (through the right caudate circuitry) of motor programs stored in the right SMA. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Handedness; Fluorodopa; Positron emission tomography; Putamen; Caudate nucleus; Supplementary motor area; Dorsolateral prefrontal cortex; Parkinson’s disease
1. Introduction Most people favor use of the right hand for performing tasks. This right motor lateralization is thought to be related, at least partly, to higher cerebral functions, particularly language representation areas on the left brain hemisphere [15]. Although handedness could have a genetic basis, studies of heritability have provided no definite result [12,27]. Other factors may, therefore, influence handedness [16]. It is noteworthy that animals also show forelimb preference [17,22,39]. It has long been proposed that asymmetries of the nigrostriatal dopamine system are related to asym-
* Corresponding author. Tel.: +1-604-8227935; fax: + 1-6048227866. E-mail address: [email protected] (A.J. Stoessl)
metries in motor preference. Thus, there seem to be small differences between left and right striatal dopamine levels that could reflect spatial preferences in rats [17,39]. In humans, conflicting results have been reported, but there do seem to be higher amounts of dopamine in the left globus pallidus than in the right [18,32]. In addition, the size of the left globus pallidus has been found to be larger than the right [25]. However, the main target of the nigrostriatal dopamine system is not the globus pallidus but the striatum (caudate and putamen) [1–4,14,21]. To date, no definite nigrostriatal asymmetries have been linked to handedness. Handedness may be a graded characteristic and, therefore, both qualitative and quantitative data on hand preference are needed to evaluate whether asymmetries in the nigrostriatal dopamine system relate to motor lateralization. Furthermore, the caudate and
0166-4328/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 6 - 4 3 2 8 ( 0 0 ) 0 0 1 6 5 - 0
64
R. de la Fuente-Ferna´ndez et al. / Beha6ioural Brain Research 112 (2000) 63–68
putamen are likely to have different functions. There is good evidence that the putamen is predominantly involved in motor execution; the caudate nucleus, on the other hand, seems to play a role in motor planning and motor learning [1– 4,14,21]. We hypothesized that whereas hand preference would be related to side-toside asymmetries in putamen dopaminergic activity, asymmetries in caudate dopaminergic activity might correlate with the performance of complex movements (e.g. bimanual movements). To explore these hypotheses we examined in vivo the nigrostriatal dopamine system using fluorine-18-6-fluorodopa (FD) positron emission tomography (PET). Several studies have shown that FD PET is a reliable [38] and useful tool for exploring the nigrostriatal dopaminergic projection [34]. The FD uptake rate constant (Ki ), which represents the trapping of FD in the nigrostriatal terminals, is highly correlated with striatal dopamine levels [34]. It is not clear if left-handedness represents a situation opposite to that seen in right-handers, or simply a loss of the usual brain asymmetry. Anatomical and functional studies have shown that the degree of brain asymmetry is much less striking in left-handers compared to right-handers [15,23]. The situation in individuals with no clear hand preference (ambidextrous) could be even more complex. Therefore, we focused our study on individuals with a clear right hand preference [29]. The degree of motor lateralization and ability to perform simultaneous bimanual movements were measured by using the Purdue pegboard test (PPBT) [36]. Left –right asymmetries in caudate and putamen Ki values, and asymmetries in right – left PPBT were calculated using normalized values. We expected to find left putamen dominance on unilateral PPBT, and left caudate dominance on bilateral PPBT.
2. Materials and methods
2.1. Subject selection We studied 20 right-handed normal volunteers. There were nine men and 11 women, aged 479 17 years (mean 9SD). All normal subjects reported right-hand preference in everyday activities [29], and the neurological examination was entirely normal in all of them. We also studied 19 right-handed patients with asymmetric Parkinson’s disease (PD). All patients satisfied the clinical criteria for definite PD [11]. In the patient group there were 12 men and seven women, aged 56 9 9.7 years (mean9 SD). All patients were evaluated between 08:00 and 10:00 h after at least 12 h of withdrawal of medications. The severity of parkinsonism was evaluated using the Modified Columbia Scale (MCS) score [13] and the PPBT [36]. Parkinsonism was defined as asymmetric when the difference between the right and
left MCS score was of more than 1 point, and there was at least 1 point difference between right and left PPBT. All clinical assessments (including the PPBT) were performed prior to the PET scans.
2.2. PPBT The PPBT [36] records the number of pegs inserted into a pegboard in 30 s unilaterally with each hand separately and bilaterally with both hands simultaneously. An experienced technician performed the test. We chose the PPBT to assess the degree of motor lateralization because this test has been found to correlate with striatal Ki in PD [37].
2.3. FD PET All PET studies were performed using an ECAT 953B/31 tomogragh in 2D mode. The details of the protocol have been described elsewhere [38]. The subject was positioned with the image plane parallel to the orbito-meatal line. A thermo-plastic face mask was molded to restrain head movement. Tissue attenuation was measured for later use in attenuation correction. Subjects received an injection of 5 mCi of FD 1 h after premedication with 150–200 mg of carbidopa. Twelve sequential emission scans, each lasting 10 min, were performed starting at the midpoint of the FD injection. Activity collected from 60 to 120 min after FD administration was summed to produce an integral image. On this image regions of interest (ROIs) were placed. A small circular ROI (diameter 8.8 mm) was positioned by inspection on each caudate nucleus and three circular ROIs (diameter 8.8 mm) were place without overlap along the axis of each putamen. The ROIs were adjusted on the integral image to maximize the average ROI activity. Three background circular ROIs (diameter 19.4 mm) were placed on the parieto-occipital cortex. This was repeated for the five slices where the caudate and putamen were most clearly seen, and replicated over 12 time frames. The tissue data were analyzed by the graphical method described by Patlak and Blasberg [31] on the values from 20 to 120 min using the cortical input function [10]. FD uptake rate constants (Ki ) were calculated for the right and left caudate and putamen. Subjects gave written informed consent. The study was authorized by the UBC Ethics Committee.
2.4. Statistical analysis Normalized left–right differences for caudate and putamen Ki were calculated using the formula: (left− right)/(1/2 × (left+ right)). Similarly, normalized right– left asymmetries in PPBT hand performance were calculated by the formula: (right−left)/(1/2 ×(right+
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left)), which gives an objective estimate of the degree of right hand preference. Four correlation analyses were decided in advance: correlation of right – left PPBT asymmetry with left– right asymmetries in putamen and caudate Ki, and correlation of bilateral PPBT score with left–right asymmetries in caudate and putamen Ki. Parametric and non-parametric statistical methods were used as appropriate; two-tailed P-values B0.05 were considered as statistically significant. 3. Results
3.1. Normal 6olunteers There were no left – right differences (paired t-test) for caudate Ki (mean9 SD, 0.00959 0.001 versus 0.00909 0.001, P = 0.16) or putamen Ki (mean 9 SD, 0.008090.001 versus 0.0080 90.001, P =0.93). Females and males had similar Ki values for both caudate and putamen (Table 1). Table 1 Values (mean 9 SD) of [18F]fluorodopa uptake constant (Ki ) (ml·min−1·cc−1) in right-handed normal volunteersa Right caudate
Left caudate
Right putamen
Left putamen
Male
0.0088 90.001
0.0092 90.001
0.0079 9 0.001
0.0080 90.001
Female
0.0092 90.001
0.0097 90.001
0.0081 9 0.002
0.0080 9 0.001
a
t-Test, P\0.2 for all comparisons.
Fig. 1. Degree of right hand preference as estimated by unilateral PPBT (see Section 2) plotted against left–right putamen Ki asymmetry in right-handed normal subjects (horizontal axis, values to the right and left of the zero score represent left and right putamen dominance, respectively). A significant correlation was observed (Spearman rank correlation coefficient: r = 0.64, P= 0.0026). Caudate Ki asymmetry did not correlate with right hand preference (Spearman rank correlation coefficient: r= 0.014, P= 0.95).
Fig. 2. Simultaneous bimanual movements (bilateral PPBT score) plotted against left – right caudate Ki asymmetry for right-handed normal subjects (a) and right-handed patients with Parkinson’s disease (b). Again, values to the right and left of the zero score of the horizontal axis represent left and right caudate dominance, respectively. Regression analysis showed a significant inverse correlation in both cases (for normal subjects: r = −0.76, P=0.00010; for patients: r = −0.60, P=0.0066). In normal subjects, putamen Ki asymmetry did not correlate with bilateral PPBT score (r =0.33, P =0.15).
As expected, we observed that asymmetries in right– left PPBT correlated positively with left–right asymmetries in putamen Ki (Spearman rank correlation coefficient: r= 0.64, P= 0.0026) (Fig. 1). No such correlation was found for caudate (Spearman rank correlation coefficient: r= 0.014, P= 0.95). We also found that, whereas left–right putamen Ki asymmetry did not correlate with simultaneous bilateral hand performance (bilateral PPBT) (r=0.33, P= 0.15), caudate Ki asymmetry correlated negatively with bimanual movements (r= − 0.76, P= 0.00010) (Fig. 2a). In other words, contrary to our prediction, our results suggest that is the right caudate, and not the left, that plays a dominant role in motor control in right-handed subjects.
3.2. Patients with PD To evaluate further the role of the caudate nucleus in bimanual movement performance, we next studied patients with PD. PD is characterized by extensive dam-
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age to the nigrostriatal dopamine system, the putamen being considerably more affected by dopamine deficiency than the caudate nucleus [8,24]. In addition to difficulty in performing simple movements, PD patients have more difficulty when they attempt to execute bilateral coordinated movements [6,7]. The occurrence of asymmetric motor signs is an almost constant feature of PD [26]. Therefore, the study of PD offers an opportunity to explore whether the caudate nucleus plays a crucial role in bimanual movements. Based on our findings in normal subjects we expected to find a greater bilateral PPBT score in patients with higher right than left caudate Ki (adjusting for differences in disease severity, irrespective of which body side is clinically more affected). Twelve patients showed right-predominant parkinsonism, and seven left-predominant parkinsonism. In all cases the most affected body side had also been the side in which symptoms had started. Regression analysis showed that caudate Ki asymmetry correlated negatively with bilateral PPBT score both before (r= − 0.60, P =0.0066) (Fig. 2b), and after adjusting for severity of parkinsonism (including in the regression model either total striatum Ki (P = 0.0043) or MCS score (P=0.026) as variables measuring overall severity of parkinsonism). As predicted, patients with higher right than left caudate Ki (n = 12) were found to perform much better in bilateral PPBT than those in whom the Ki value of the left caudate was higher than that of the right (n= 7) (mean9SD, 18.4293.82 versus 11.14 94.85; independent-samples t-test value = 3.63, P=0.0021). This difference remained significant after adjusting for between group differences in severity of parkinsonism by analysis of covariance (ANCOVA) (using either total striatum Ki (P = 0.0038) or MCS score (P=0.0033) as covariates).
4. Discussion This study provides in vivo evidence suggesting that asymmetries in the nigrostriatal dopaminergic system may play a role in motor lateralization in humans. Because the striatal FD uptake constant (Ki ) correlates highly with striatal dopamine levels [34], we can use the Ki values as a good estimate for the underlying levels of dopamine. We found that the degree of right hand preference, as estimated objectively by the PPBT, increased with left putamen dopaminergic dominance in right-handed subjects. This suggests that in righthanded subjects, the levels of dopamine are higher in the left putamen than in the right. Similarly, previous post mortem studies have reported left-biased levels of dopamine in the lateral globus pallidus [18]. However, we did not find a significant difference in mean Ki values between the left and right sides, suggesting that
the effect is graded rather than absolute. Furthermore, our results suggest that brain lateralization related to handedness may be more complex than expected. Indeed, it was the right caudate, not the left, that was found to play a dominant role in controlling simultaneous bimanual movements. As previously noted by others [28] the degree of handedness may be taskcontingent. Current available data allow us to integrate our findings in a model. It is thought that the supplementary motor area (SMA), which receives input from the putamen [1–4,14,21], is involved in motor programming [20,30,35]. The caudate nucleus, on the other hand, receives input from, and projects (via the globus pallidus and thalamus) back to the dorsolateral prefrontal cortex [1–4,14,21]. Although the function of the dorsolateral prefrontal cortex remains obscure, it is known that this cortical region is connected with the SMA [5]. According to current models the basal ganglia circuitry acts to modulate the excitatory thalamocortical output. We propose that the skill for performing simultaneous bilateral hand movements in right-handed subjects might depend upon the activation (through the dominant left putamen–globus pallidus–thalamocortical loop) of motor programs stored in the left SMA, while motor programs stored in the right SMA are suppressed by the right-caudate dependent projection from the dorsolateral prefrontal cortex. In other words, whereas the net effect of stimulating putaminal dopamine receptors would be excitation of the motor cortex, stimulating dopamine receptors in the caudate nucleus would lead to inhibition. Several clinical observations support this hypothesis. Thus, whereas lesions in putamen are associated with contralateral loss of motor function [9], caudate lesions lead to contralateral spontaneous abnormal movements (hyperkinesia, dyskinesia, chorea) or generalized motor hyperactivity [9]. In PD, dopamine depletion is much more severe in the putamen than in the caudate, and so loss of movement (akinesia, bradykinesia) occurs. It is relevant that in patients with PD studies of cerebral blood flow reveal reduced activation of the SMA, which is associated with relative overactivity in lateral premotor regions [33]. After partial restoration of the nigrostriatal dopaminergic transmission by levodopa treatment, many PD patients experience dyskinesias. It is not clear whether the caudate-dependent circuitry plays a major role in the pathogenesis of drug-induced dyskinesias. We have no research methods to address the question of cause versus effect. The asymmetric indices of dopaminergic brain function that we report here could play a causal role in determining handedness, but they could, equally, be the result of long term asymmetric use. Nevertheless, our study does provide some evidence supporting the existence of a cause–effect link. Thus, although (due to the damage to the nigrostriatal
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dopaminergic system that occurs in PD) motor performance was worse in patients with PD than in normal subjects, similar correlations between caudate Ki asymmetry and bilateral PPBT were found in both groups of subjects. Finally, we recognize that by using PPBT we analyzed essentially self-paced freely chosen movements. Hence, the basal ganglia functional model proposed here may not apply to other types of movements [19,28].
Acknowledgements This work was funded by the National Parkinson Foundation (Miami), the Medical Research Council of Canada, the Parkinson Foundation of Canada, and the Pacific Parkinson Research Institute (Vancouver, BC, Canada). R. de la Fuente-Ferna´ndez was supported in part by a grant from the Xunta de Galicia, Spain. We are grateful to the members of the UBC/TRIUMF PET team.
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