# The metabolic substrates of bradykinesia and tremor in uncomplicated Parkinson's disease.

Catherine Lozza, Marie Rose Moro, Jean-Claude Baron

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Catherine Lozza, Marie Rose Moro, Jean-Claude Baron. The metabolic substrates of bradykinesia and tremor in uncomplicated Parkinson's disease.. NeuroImage, 2002, 17 (2), pp.688-99.
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# The Metabolic Substrates of Bradykinesia and Tremor in Uncomplicated Parkinson's Disease

C. Lozza,*† R-M. Marié,*†‡ and J-C. Baron*§<fnref n="1" />

*INSERM U320, Centre Cyceron, Caen, France; ‡Service de Neurologie Déjérine, CHU Côte de Nacre, Caen, France; †Equipe Processus Exécutifs et Attentionnels, Université de Caen, Caen, France; and §Department of Neurology, University of Cambridge, Cambridge, United Kingdom

Received October 23, 2001

The pathophysiological mechanisms of bradykinesia and resting tremor, i.e., two major features of Parkinson's disease (PD), remain incompletely understood despite extensive studies, including functional imaging investigations. Using high-resolution positron emission tomography (PET) and [¹⁸F]fluoro-2-deoxyglucose (FDG) in 17 nondemented patients with uncomplicated PD on a stable therapeutic regimen, we measured the resting-state cerebral metabolic rate of glucose (CMRGlc), a validated marker of synaptic density/activity. Following formulation of distinct a priori hypotheses about potentially involved brain regions based on previous experimental and clinical literature, correlations between CMRGlc and objective scores of bradykinesia and tremor were searched in a voxel-based fashion using SPM99. Bradykinesia scores were significantly positively correlated with bilateral putamen and globus pallidum CMRGlc, while tremor scores were negatively correlated with bilateral putamen and cerebellar vermis CMRGlc. There was a large overlap of putamenal voxels significantly but inversely correlated with both extrapyramidal features. For both bradykinesia and tremor, the observed patterns of subcortical correlations largely concurred with our a priori hypotheses, and point to the major role of disruption of the striatofrontal and corticocerebellar pathways in the genesis of these extrapyramidal features. The direction of these correlations was not entirely expected, however, which may be due to the patients' being studied on medication, contrary to most studies performed to date. The observation that overlapping portions of the putamen inversely correlated with bradykinesia and tremor was a novel and striking finding which points to the complexity of the underlying pathophysiology of PD. Because it allows greater control of the neurological status, studying patients on medication may partly explain our findings. Voxel-based analysis of resting FDG-PET holds considerable potential for assessing the neural substrates of motor impairment in PD. © 2002 Elsevier Science (USA)

## INTRODUCTION

Although bradykinesia and resting tremor are two cardinal features of Parkinson's disease (PD), their neural mechanisms still remain incompletely understood. Clinical observation shows that these two extrapyramidal features can have dissociated severity and distribution as well as differential response to medication and deep brain stimulation, suggesting their pathophysiology is at least partly distinct. The main pathologic feature of PD is a massive dopaminergic (DA) neuron loss in the substantia nigra pars compacta (SNpc), resulting in DA denervation of the striatum. This in turn induces a demodulation of complex motor circuits comprising the motor and premotor (PM) cortices, the putamen, the globus pallidum (GP), the subthalamic nucleus, and the thalamus (Alexander and Crutcher, 1990). However, it has recently become clear that these motor circuits have extremely complicated physiology and pathophysiology (Graybiel, 2000), and the way by which striatal DA denervation disrupts the function of these interconnected structures to produce bradykinesia and resting tremor remains debated (Obeso *et al.*, 2000).

Positron emission tomography (PET) is a well-established method to assess the neural basis of motor dysfunction in PD (Brooks, 1999). Apart from the activation paradigm which maps brain activity during task performance, resting-state studies of the cerebral metabolic rate of glucose (CMRglc) with [¹⁸F]fluoro-2-deoxyglucose (FDG-PET) are of considerable interest because the CMRglc is a marker of integrated local synaptic activity and as such is sensitive to both direct neuronal/synaptic damage and secondary functional disruption at synapses distant from the primary site of pathology (Magistretti *et al.*, 1999). In neurodegeneration

<footnote n="1">¹ To whom correspondence should be addressed at Department of Neurology, University of Cambridge, Addenbrooke's Hospital, Box 83, Cambridge CB2 2QQ, UK. Fax: 44 1223 217909. E-mail: jcb54@cam.ac.uk.</footnote>
tive disorders such as Alzheimer's disease, FDG-PET has been successfully used to map the brain areas whose damage/dysfunction underlies cognitive impairment, according to a correlational approach (Desgranges *et al.*, 1998, 2002; Eustache *et al.*, 2001).

Early FDG-PET studies in PD revealed mild but significant increases in resting CMRglc in the lenticular nucleus (especially the GP) (Rougemont *et al.*, 1984; Martin *et al.*, 1984; Ohye *et al.*, 1991), consistent with the expected increase in striatopallidal synaptic terminal activity as a result of nigrostriatal DA denervation (Baron, 1994). Using the scaled subprofile model (SSM)—a method based on principal component analysis of region-of-interest (ROI) data—Eidelberg *et al.* (1990, 1994) subsequently reported a metabolic topographic profile linked to parkinsonism and comprising a relative hypermetabolism of the lentiform nucleus, thalamus, and pons cova-rying with a relative hypometabolism of the lateral frontal cortex, so-called “Parkinson's disease-related profile” (PDRP). These findings are partly consistent with resting 2-[$^{14}$C]deoxyglucose autoradiographic studies in animal models of PD. Thus, rats with unilateral 6-hydroxydopamine (6-OHDA) lesion of the SNpc show mild CMRglc reductions in the ipsilateral striatum but large CMRglc increases in the ipsilateral GP (Kozlowski and Marshall, 1980; Wooten and Collins, 1981), while hemiparkinsonian MPTP monkeys exhibit metabolic increases in putamen, caudate, and external GP and decreases in subthalamic nucleus and PM cortex (Palombo *et al.*, 1990).

Few studies have directly assessed the relationships between resting CMRglc and motor scores in PD. Ohye *et al.* (1991) assessed patients with particularly severe motor impairment unresponsive to drug therapy, and found an association between a high rCMRglc in the basal ganglia and tremor-type PD patients, but correlations were not performed. Bohnen *et al.* (1999) reported significant inverse correlations between visual cortex CMRglc asymmetry index and side-to-side asymmetries in finger-tapping performance in PD. Applying their above-mentioned SSM analysis in parkinsonian patients off DA medication (to be referred to as the “OFF” state in what follows, in contrast to the medicated, “ON”, state), Eidelberg *et al.* (1994) reported significant correlations between PDRP and bradykinesia scores, such that the more severe the bradykinesia the more marked the PDRP; correlations between tremor and PDRP scores were not significant. In a subsequent study also using SSM but this time comparing patients with predominant tremor to patients with predominant bradykinesia, Antonini *et al.* (1998) reported a topographic profile specific to tremor, which partially overlapped with the PDRP and was characterized by relative hypermetabolism of the pons, thalamus, and PM cortex.

The above PET studies, however, used the ROI method, which leaves unexplored substantial areas of the brain, has limited reproducibility and objectivity,

and often merges in a single value physiologically distinct structures, e.g., the putamen and the GP, potentially obscuring important findings (Eidelberg *et al.*, 1994; Antonini *et al.*, 1998). Except that of Bohnen *et al.* (1999), all these studies were performed in the OFF state, in which all dopaminergic medication is withdrawn at least 12 h before scanning. Studying PD patients in Hoehn–Yahr stages II–IV, Berding *et al.* (2001) found significant correlations between increasing UPDRS scores and decreases in FDG uptake in both frontal cortices and the mesial temporal lobe on the right side in the ON state, whereas no correlation was found in the OFF state. These results suggest that the ON state may also be interesting to study associations to motor scores in PD.

Studies using the activation paradigm in PD have been globally consistent with the resting CMRglc studies, showing an involvement of the lateral PM cortex, putamen, and supplementary motor area (SMA) in bradykinesia (Playford *et al.*, 1992; Rascol *et al.*, 1994; Samuel *et al.*, 1997), and of the cerebellar vermis, striatum, and thalamus in tremor (Parker *et al.*, 1992; see Brooks, 1999, for review). Overall, therefore, both the animal and the clinical literature point to a well-defined set of interconnected brain regions involved in the bradykinesia and tremor of PD.

In the present work, we assessed the relationships between tremor and bradykinesia scores, on one hand, and resting CMRglc data, on the other hand, all obtained in the ON state in patients with stable and uncomplicated PD. To map these relationships, we used a voxel-based rather than ROI approach, namely, SPM (Friston *et al.*, 1991), which systematically and objectively searches the entire brain volume examined and allows an anatomical localization based on the stereotaxic atlas of the human brain (Talairach and Tournoux, 1988). Although the above literature would not allow making precise predictions about which structures exactly are involved in tremor and bradykinesia and which would be the direction of correlations with CMRglc, one would nevertheless predict that, apart from the SNpc itself, the involved regions should comprise the basal ganglia, the thalamus, and the lateral PM cortex for both bradykinesia and tremor, and the SMA and the cerebellar vermis specifically for bradykinesia and tremor, respectively. For this subset of structures, a less conservative, hypothesis-driven cut-off for statistical significance is therefore used in the present voxel-based analysis.

## METHODS

### *Patients*

We studied 17 patients (13 men, 4 women; mean age of 59 ± 8 years) (see Table 1) selected according to the following criteria: probable PD according to the criteria of
<table><caption>TABLE 1
Clinical Characteristics</caption><thead><tr><th rowspan="2">No./sex/age</th><th rowspan="2">Disease duration (years)</th><th rowspan="2">Hoehn and Yahr score</th><th colspan="2">Treatment<sup>a</sup></th><th colspan="3">Tremor<sup>b</sup></th><th colspan="3">Bradykinesia<sup>b</sup></th></tr><tr><th>L-DOPA</th><th>AG</th><th>Right</th><th>Left</th><th>Total score</th><th>Right</th><th>Left</th><th>Total score</th></tr></thead><tbody><tr><td>1/M/70</td><td>1</td><td>1</td><td>+</td><td>-</td><td>0</td><td>6</td><td>6</td><td>0</td><td>5</td><td>6</td></tr><tr><td>2/M/68</td><td>11</td><td>3</td><td>+</td><td>-</td><td>4</td><td>4</td><td>8</td><td>4</td><td>3</td><td>16</td></tr><tr><td>3/M/59</td><td>14</td><td>2</td><td>+</td><td>+</td><td>3</td><td>0</td><td>3</td><td>8</td><td>3</td><td>16</td></tr><tr><td>4/M/59</td><td>6</td><td>2</td><td>+</td><td>+</td><td>0</td><td>0</td><td>0</td><td>1</td><td>4</td><td>11</td></tr><tr><td>5/M/58</td><td>15</td><td>2</td><td>+</td><td>-</td><td>1</td><td>1</td><td>2</td><td>1</td><td>5</td><td>8</td></tr><tr><td>6/M/46</td><td>9</td><td>2</td><td>+</td><td>+</td><td>0</td><td>0</td><td>0</td><td>4</td><td>2</td><td>8</td></tr><tr><td>7/F/65</td><td>3</td><td>2</td><td>+</td><td>-</td><td>2</td><td>0</td><td>2</td><td>8</td><td>2</td><td>12</td></tr><tr><td>8/M/47</td><td>4</td><td>2</td><td>+</td><td>+</td><td>0</td><td>3</td><td>3</td><td>1</td><td>4</td><td>7</td></tr><tr><td>9/M/64</td><td>14</td><td>2</td><td>+</td><td>-</td><td>1</td><td>4</td><td>5</td><td>4</td><td>7</td><td>14</td></tr><tr><td>10/F/40</td><td>14</td><td>2</td><td>+</td><td>+</td><td>3</td><td>5</td><td>8</td><td>3</td><td>5</td><td>10</td></tr><tr><td>11/M/67</td><td>7</td><td>1</td><td>+</td><td>-</td><td>0</td><td>0</td><td>0</td><td>1</td><td>3</td><td>7</td></tr><tr><td>12/M/65</td><td>6</td><td>2</td><td>+</td><td>-</td><td>5</td><td>2</td><td>7</td><td>8</td><td>2</td><td>13</td></tr><tr><td>13/F/51</td><td>6</td><td>1</td><td>+</td><td>-</td><td>0</td><td>0</td><td>0</td><td>1</td><td>3</td><td>5</td></tr><tr><td>14/M/68</td><td>8</td><td>2</td><td>+</td><td>-</td><td>3</td><td>0</td><td>6</td><td>6</td><td>2</td><td>9</td></tr><tr><td>15/M/65</td><td>12</td><td>2</td><td>+</td><td>+</td><td>0</td><td>0</td><td>0</td><td>6</td><td>5</td><td>16</td></tr><tr><td>16/M/55</td><td>6</td><td>2</td><td>+</td><td>+</td><td>5</td><td>0</td><td>5</td><td>3</td><td>3</td><td>8</td></tr><tr><td>17/F/58</td><td>1</td><td>1</td><td>-</td><td>+</td><td>0</td><td>3</td><td>3</td><td>1</td><td>4</td><td>7</td></tr><tr><td>Mean</td><td>8</td><td></td><td></td><td></td><td>1.6</td><td>1.6</td><td>3.4</td><td>3.5</td><td>3.6</td><td>10.2</td></tr><tr><td>SD</td><td>4.6</td><td></td><td></td><td></td><td>1.9</td><td>2.1</td><td>2.9</td><td>2.8</td><td>1.4</td><td>3.7</td></tr></tbody></table>

Gelb *et al.* (1999); age ≤70 years; ability to read and write French with >5 years of education; Hoehn–Yahr stage I–III; only L-DOPA and DA agonists allowed as antiparkinsonian therapy; lack of depression as measured by a Montgomery and Asberg Depression Rating Scale (MADRS) score below 6 (Mongomery and Asberg, 1979); lack of dementia as evaluated by the DSM-IIIr (including an MMSE above 27); Hachinski modified score ≤2; no known history of brain or thyroid gland disease, alcoholism, or use of psychotropic agents; and lack of significant MRI abnormalities apart from what would be normally expected for age. Patients with fluctuations, dyskinesia, or on-off phenomena were excluded. Following at least 1 month of stable dopaminergic treatment with optimal clinical benefit, the PET study was performed in the early afternoon, in the ON state.

The Columbia modified scale was given the day before the PET study, in the early afternoon and while on medication, i.e., exactly at the same time and under the same medication-related conditions as for PET scanning. This scale scores bradykinesia and tremor for each limb on each side of the body as well as axially in the seated and upright positions and while walking. Scores range from 0 (no abnormality) to 4 (maximum disability). The bradykinesia and tremor global scores are the sums of these component scores, and thus range from 0 to 20.

## PET Methodology

CMRglc was measured in a resting state, with eyes closed and in dimmed light with reduced ambient

noise, using FDG, according to a standard methodology detailed in Penniello *et al.* (1995). The PET study commenced around 2:00 PM, the last dose of oral DA medication being taken at noon. PET acquisition was started only after the patient had relaxed, and especially after any stress-related increase in tremor had eased. Behavior was qualitatively observed at intervals by a neurologist (R-M.M.). No significant abnormal movements were noted. We used a seven-plane PET device (intrinsic resolution for ¹⁸F: 5.5 × 5.5 × 9 mm, x y z, with a field of view of 81 mm; Model TTV 03 LETI) (Mazoyer *et al.*, 1990). Photon attenuation correction was carried out by means of a ⁶⁸Ga–⁶⁸Ge transmission scan. Positioning was performed according to the stereotaxic method of Fox *et al.* (1985), which allowed us to obtain cuts essentially parallel to the biocommissural line (from −4 to +68 mm relative to this line). During data acquisition, head displacement was monitored and, if necessary, corrected thanks to light beams projected onto the subject’s forehead.

Following transmission scans, 111–222 MBq of FDG was injected as a bolus and 20 arterial blood samples were withdrawn to measure ¹⁸F plasma concentrations and plasma glucose content. The seven PET planes, acquired from 50 to 60 min after injection, were transformed pixel by pixel into parametric maps of CMRglc according to Phelps *et al.* (1979).

## Image Processing

The PET data were implemented on a SUN workstation. SPM99 (Statistical Parametric Mapping; Well-

<footnote><sup>a</sup> L-DOPA, levo dopa; AG, dopaminergic agonist.</footnote>

<footnote><sup>b</sup> From the Colombia modified scale, measured while in the ON state.</footnote>
come Department of Cognitive Neurology, London, UK) software was used to reorient and spatially normalize each PET data set onto the standard MNI (Montreal National Institute) template contained in SPM99. Manipulations of the image matrix and statistical calculations were carried out with MATLAB (Mathworks, Sherborn, MA). To minimize edge effects, values >80% of whole-brain mean were selected for statistical analysis. The images were filtered with a 16-mm three-dimensional Gaussian filter to attenuate anatomical interindividual differences and reduce data noise. Resliced data sets had a 4-mm slice thickness matching Talairach and Tournoux's atlas. Given the limited field of view (84 mm) of the PET device used, the brain could not be studied in its entire axial extent (see Desgranges et al., 1998, for a detailed account and discussion of this). The statistical analysis was processed with SPM99 using the general linear model (Friston et al., 1995). To control for intersubject variability in global CMRglc, normalization of the PET data by the average CMRglc across all selected voxels was carried out using the proportional scaling routine. These are referred to as nCMRglc in what follows.

## Statistical Analysis

**1. Global scores.** We used SPM99 to perform correlations between nCMRglc, on one hand, and the tremor and bradykinesia global scores, on the other hand. To assess the correlations with CMRGlc specific to bradykinesia and tremor separately, both scores for each patient were entered as covariates of interest in the SPM matrix, and a regression analysis was performed for each score independently of the other. Thus, all the correlations presented here between nCMRGlc and tremor or bradykinesia have been computed taking into account the effect of the other clinical variable. The SPM maps were thresholded at $Z \ge 2.33$ ($P \le 0.01$). Taking into account our a priori hypothesis (see Introduction), we considered as statistically significant any correlation that both involved these brain structures (namely, the PMC, putamen, and SMA for bradykinesia, and the cerebellar vermis, striatum, and thalamus for tremor) and reached the hypothesis-driven cutoff of $P < 0.005$ (Desgranges et al., 2002). Peaks concerning brain structures other than those just listed were considered significant if they reached the more conservative, exploratory cutoff of $P < 0.05$, cluster level corrected.

The clusters of significantly correlated voxels were mapped onto the standard MRI template of SPM99, and stereotaxic coordinates of the peaks for each cluster were obtained both as SPM99 and as Talairach and Tournoux based on M. Brett's transforms (see web site http://www.mrc-cbu.cam.ac.uk/Imaging/mnispace.htm). To identify geographically overlapping clusters, i.e., voxels that significantly correlated with both bra-

dykinesia and tremor, we used an in-house routine denominated "SPM-merge," which is based on the Analyze and SPM softwares and is identical to the Add Blobs command in SPM99, though allowing a better-quality display (see Fig. 3). Thanks to this routine, it was possible to simultaneously display on the standard MRI template and in distinct colors the significant clusters for each contrast, while the overlapping voxels, if any, would be displayed in the blend color.

**2. Lateralized scores.** In addition to the main analysis of tremor and bradykinesia global scores, an ancillary correlative analysis was also carried out using the lateralized motor scores, i.e., taking each side of the body independently. As with the analysis of global scores, both the tremor and bradykinesia lateralized scores were entered as covariates in the SPM design matrices (right- and left-sided scores separately), SPM maps were generated using the $Z \ge 2.33$ threshold, and both hypothesis-driven and exploratory cutoffs were used in the interpretation of the SPM results as described above. The findings with this analysis are presented for the sake of completeness only.

## RESULTS

### Clinical Data

The relevant clinical data are listed in Table 1. All 17 patients had some degree of bradykinesia, while 5 had no significant tremor. There was no significant correlation between tremor and bradykinesia global scores across the patient group (Pearson's $r = 0.225$, $P = 0.39$). All patients had bilateral impairment. However, tremor predominated on the left and right sides of the body in five patients each. Patient 14 had some head tremor in addition to limb tremor, which explains his higher global score. Apart from the five patients who had no tremor, the asymmetry of bradykinesia was broadly consistent with that of tremor in some patients but was strikingly different in others (see Table 1).

### SPM Findings

**Global scores.** The results are given in Table 2. Using the approach described above, there were no significant findings with the exploratory cutoff, but five correlations concerning structures that were part of our hypotheses reached the hypothesis-driven cutoff of $P < 0.005$, uncorrected. Scatterplots for these five hypothesis-driven correlations are shown in Fig. 1.

Regarding bradykinesia, all correlations were positive, such that the worse the bradykinesia, the higher the nCMRglc. They concerned the putamen bilaterally ($P < 0.001$ for both sides), extending into the GP on both sides (Fig. 2). Regarding tremor, all the significant correlations were in the negative direction, such that the more severe the tremor, the lower the nCMRglc.
<table><caption>**TABLE 2**
Significant Correlations between Bradykinesia and Tremor Global Scores, on One Hand, and nCMRglc on the Other Hand, as Provided by SPM99<sup>a</sup></caption><thead><tr><th>Region</th><th>Talairach<br>coordinates<br>(x, y, z)</th><th>Peak Z score</th><th>Cluster<br>size</th><th>P value<br>(uncorrected)</th></tr></thead><tbody><tr><td colspan="5" style="text-align: center;">Bradykinesia (positive contrast)</td></tr><tr><td>Putamen R</td><td>24, -9, 8</td><td>3.50</td><td>402</td><td>0.000</td></tr><tr><td>Putamen L</td><td>-30, -11, 8</td><td>3.46</td><td>473</td><td>0.000</td></tr><tr><td colspan="5" style="text-align: center;">Tremor (negative contrast)</td></tr><tr><td>Putamen L</td><td>-30, -7, 8</td><td>3.50</td><td>126</td><td>0.000</td></tr><tr><td>Cerebellar vermis</td><td>-8, -43, -5</td><td>2.91</td><td>67</td><td>0.002</td></tr><tr><td>Putamen R</td><td>30, -13, 8</td><td>2.66</td><td>95</td><td>0.004</td></tr></tbody></table>

<sup>a</sup> See Methods. Shown are the *x*, *y*, *z* Talairach Coordinates (see Methods), the peak Z score, the cluster size, and the corresponding *P* value. According to the approach detailed under Methods, all the correlations found concerned structures that were part of our hypothesis; i.e., they reached the *P* ≤ 0.005 cutoff. uncorrected for multiple tests.

They concerned the putamen bilaterally (*P* < 0.001 for the left putamen cluster, and *P* = 0.004 for the right putamen cluster, which extended slightly into the GP, see Fig. 3) and the cerebellar vermis (*P* = 0.002) (Table 2, Fig. 3).

As illustrated in Fig. 4, there was a large overlap of clusters in both the left and right putamens, that is, there were numerous voxels on each side of the putamen that exhibited significant but inverse correlations with both tremor scores (negative correlation) and bradykinesia scores (positive correlation).

*Lateralized scores.* The results are given in Table 3. Again, there was no significant cluster at the exploratory cutoff. Six peaks concerning structures that were part of our hypotheses reached the hypothesis-driven cutoff of *P* < 0.005, uncorrected. Two correlations with right *bradykinesia* scores, both positive, concerned the left putamen and right internal GP (*P* = 0.001 and *P* = 0.005, respectively). All four correlations with tremor were negative. Left-sided tremor correlated with right and left putamen nCMRglc (*P* = 0.003 and *P* < 0.001, respectively; the right putamen cluster extending into the GP), whereas right-sided tremor correlated with left vermis/cerebellum and right SNpc nCMRglc (*P* = 0.002 and *P* = 0.003, respectively). The cluster in the SNpc is illustrated in Fig. 5.

DISCUSSION

In this FDG-PET study of mild-to-moderate PD patients on medication, we used voxel-based image analysis and found that the severity of global bradykinesia was related to higher nCMRglc in the putamen and GP, while that of resting tremor was related to lower nCMRglc in the putamen and cerebellar vermis. Interestingly, there was an extensive zone of overlap in the putamen bilaterally, where constitutive voxels had

their nCMRglc correlating both positively with bradykinesia and negatively with tremor. The analysis of lateralized bradykinesia and tremor scores was entirely consistent with that of global scores in terms of both structures involved and direction of the relationships, but revealed one additional and interesting correlation between right tremor scores and nCMRglc of the SNpc.

Before discussing the pathophysiological implications of these findings, some methodological considerations are warranted. In this study, we elected to use a voxel- rather than ROI-based approach to image analysis because it assesses the sampled block of tissue in a systematic and comprehensive way. Our findings suggest this is an interesting approach to investigate the pathophysiology of movement disorders. One limitation of our study is that some brain regions potentially important in the pathophysiology of bradykinesia, such as the SMA, could not be analyzed due to the limited axial field of view of the PET device used. Another limitation relates to the fact that we studied our patients in the medicated state, and it could be argued that DA medication diminishes the expression of clinical signs in PD to a variable extent in each patient. Thus, using “on medication” scores for correlation with metabolic changes may be inappropriate. The logic that directed our choice for this design was fourfold: (i) sustained and adjusted oral L-dopa treatment does not significantly affect the regional distribution of CMRglc in PD (Rougemont *et al.*, 1984; Meter *et al.*, 1990) except for the thalamus and the ventro-orbital region (Broussolle *et al.*, 1993; Berding *et al.*, 2001), two brain structures known to be depleted in monoamines in PD (Marié *et al.*, 1995); although in their pharmacologically controlled study Feigin *et al.* (2001) found more extensive metabolic effects of L-DOPA, especially concerning the putamen, GP, thala-
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**FIG. 1.** Scatterplots of the five significant correlations between nCMRglc and global motor scores (see Table 2 for details). *Bradykinesia*: Regression graph of the correlation between global bradykinesia scores and adjusted nCMRglc values or the peak localized in (A) the right putamen (x, y, z = 24, -9, 8 in Talairach coordinates) and (B) the left putamen (x, y, z = -30, -11, 8 in Talairach coordinates). *Tremor*: Regression graph of the correlation between global tremor scores and adjusted nCMRglc values for the peak localized in (C) the left putamen (x, y, z = -30, -7, 8 in Talairach coordinates), (D) the cerebellar vermis (x, y, z = -8, -43, -5 in Talairach coordinates), and (E) the right putamen (x, y, z = 30, -13, 8 in Talairach coordinates). (Note that, for the sake of the illustration and in contrast to the SPM analysis presented under Results, the results of linear regression shown here for these scatterplots do not take into account the effect of covariation with the other clinical variable.)

mus, and cerebellum, this was an acute challenge study where levodopa was given in intravenous infusion; (ii) the OFF state is difficult to control, as the time needed to reach a pharmacologically and clinically stable state may unpredictably vary from patient to patient, as shown by the individual response patterns to the administration of levodopa (Fabbrini et al., 1988);

(iii) the discomfort that results from DA therapy withdrawal induces potentially confounding effects including stress, pain, and vegetative upheaval (Defer et al., 1999); and (iv) finally, as mentioned in the Introduction, Bohnen et al. (1999), but also Berding et al. (2001), lately used the ON state to assess CMRglc-motor behavior correlations. Performing a correlative
<figure><img src="image_7.png" /><figcaption>**FIG. 2.** Illustration of the correlations between nCMRglc and global bradykinesia scores: statistical parametric maps (SPMs) of significant correlations at *P* ≤ 0.01, positive contrast, shown here at the *z* = 8 mm level in Talairach coordinates, projected onto the SPM99 MRI template. Both clusters were significant at the hypothesis-driven cutoff of *P* ≤ 0.005, voxel level uncorrected (see Table 2 for details).</figcaption></figure>

study in patients scanned in both the ON and the OFF states would provide important information as to whether medication modulates the metabolic correlates of motor behavior in PD. Finally, no correlation reached the exploratory cutoff of *P* < 0.05, corrected for multiple tests, but this cutoff would be considered to lie on the conservative side; the hypothesis-driven cutoff of *P* < 0.005, uncorrected, has been used previously in similar CMRGlc-behavior correlations (Desgranges *et al.*, 2002) and appears reasonable, though it may not completely protect against chance findings.

Although it may be argued that our correlations between CMRGlc and bradykinesia and tremor scores are not valid because the latter were obtained apart from FDG-PET scanning, it would be difficult to obtain these motor scores during scanning, especially so for bradykinesia, as the validated scales are given in the sitting and upright positions. We therefore obtained our measurements of tremor and bradykinesia the day before the PET study, in the early afternoon and while on medication, i.e., exactly at the same time and under the same medication-related conditions as for PET scanning. We believe this was adequate for the purpose of this investigation, which was to relate a degree of clinical severity to pathologic changes in CMRGlc. In addition, the FDG-PET data used to calculate CMRGlc, obtained 50 to 60 min after FDG administration, integrate all behavior from time of injection, and thus are unlikely to be affected by brief changes in these clinical variables as would short perfusion scans with, e.g., H₂¹⁵O bolus injection. Also, our patients were strictly selected for lack of on-off fluctuations and dyskinesia, making rapid changes unlikely to occur, and PET scanning was delayed until any stress-related tremor increase had vanished. Nevertheless, episodic mild resting tremor may have occurred during scanning, but

was not recorded. It is unclear how this may have affected the findings or interpretation thereof.

### Bradykinesia

Our most consistent finding regarding bradykinesia was a positive correlation with putamen nCMRGlc, encroaching onto the GP. Thus, the worse the bradykinesia, the higher the CMRglc—and hence the terminal synaptic activity—in these two basal ganglia structures. Reproducibly increased striatal and pallidal CMRglc has been observed in animal models of PD, and likewise increased lenticular CMRglc has been consistently reported in PD (see Introduction). Using ROIs and principal component analysis, Eidelberg and colleagues reported a positive correlation between ratings of bradykinesia and increased relative metabolism of the lenticular nucleus ROI (comprising both the putamen and the GP) (Eidelberg *et al.*, 1994; Moeller *et al.*, 1999). Our observations would be consistent with this earlier finding, though shown here with a voxel-

<figure><img src="image_8.png" /><figcaption>**FIG. 3.** Illustration of the correlations between nCMRglc and global tremor scores: statistical parametric maps (SPMs) of significant correlations at *P* ≤ 0.01, negative contrast, shown here at the *z* = 8 mm and *z* = -5 mm levels in Talairach coordinates (A and B, respectively), projected onto the SPM99 MRI template. All clusters shown were significant at the hypothesis-driven cutoff of *P* ≤ 0.005, voxel level uncorrected (see Table 2 for details).</figcaption></figure>
<figure><img src="image_9.png" /><figcaption>FIG. 4. Illustration of the overlap of voxels significantly correlated with both bradykinesia and tremor global scores projected onto the standard MRI template of SPM99 (at the axial level *z* = 8 mm in Talairach coordinates). In this illustration, obtained with Analyze software from the SPM99 data, the significant clusters obtained for the bradykinesia-nCMRGlc correlation (positive contrast) and the tremor-nCMRGlc correlation (negative contrast) are displayed in yellow and blue, respectively, while the overlapping voxels are displayed in the blend color, i.e., green.</figcaption></figure>

based analysis and concerning each component of the
lenticular nucleus separately.

Regarding specifically the GP, both its involvement
here and the direction of the correlation are consistent
with the fact that bradykinesia is improved not only by
stereotactic pallidotomy (Iacono *et al.*, 1994) but also by
pallidal deep-brain stimulation, which is known to re-
sult in reduced pallidal neuron firing rate (Davis *et al.*,
1997). Furthermore, Eidelberg *et al.* (1996) reported
significant and positive correlations between preoper-
ative lentiform metabolism on the intended pal-
lidotomy side and both intraoperative pallidal firing
rates and postoperative contralateral clinical improve-
ment (including bradykinesia assessment). Our finding
therefore likely reflects the abnormally increased firing
of both the striatopallidal GABAergic and the sub-
thalamic–pallidal glutamatergic pathways in PD (Al-
bin *et al.*, 1989), and further highlights the role of
functional imbalance in the GP in the pathogenesis of
bradykinesia.

Regarding the putamen, the transcription of the cas-
cade of events consecutive to dopamine depletion in
terms of glucose utilization appears considerably more
complex than for the GP. The functional organization
of the striatum is in need of refinement, with several
recent observations, such as functional differences be-

tween striosome and matrix neurons (Graybiel, 2000),
and D1 and D2 receptor colocalization on striatal neu-
rons involved in the direct and indirect pathways (Aiz-
man *et al.*, 2000), as yet not fully incorporated in the
model (Gerfen, 2000; Olanow *et al.*, 2000).

Tremor

Our finding of a significant correlation between tremor scores and nCMRGlc of the putamen and cerebellar vermis is consistent with our working hypothesis about the implication of the striatocortical and cerebellocortical motor loops in this extrapyramidal feature. As detailed in the Introduction, the nigrostriatal pathway and the cerebellum both belong to the distributed neural network thought to be involved in tremor (Elble, 2000). Studies in nonhuman primates exposed to MPTP or harmaline accordingly suggest that parkinsonian tremor results from a combination of dysfunctional nigrostriatal (Eberling *et al.*, 2000) and cerebellar (Poirier *et al.*, 1966) systems.

To our knowledge, there is no previous PET study of
the regression between resting tremor and resting

<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /><figcaption>**FIG. 5.** SPM99 correlation between nCMRglc and right tremor scores, illustrating in the axial (A: *z* = -4 mm, Talairach) and sagittal (B: *x* = 10 mm, Talairach) planes the significant cluster in the right substantia nigra (*P* < 0.005, voxel level uncorrected; negative contrast; peak marked with the blue cross), projected onto the SPM99 MRI template (see Table 3 for details).</figcaption></figure>
<caption>TABLE 3</caption>

Significant Correlations between Bradykinesia and Tremor Lateralized Scores, on One Hand, and nCMRglc, on the Other Hand, as Provided by SPM99<sup>a</sup>

<table><thead><tr><th>Region</th><th>Talairach coordinated (x, y, z)</th><th>Peak Z score</th><th>Cluster size</th><th>P value (uncorrected)</th></tr></thead><tbody><tr><td colspan="5">Bradykinesia R (positive contrast)</td></tr><tr><td>Putamen (L)</td><td>-22, 10, -4</td><td>3.06</td><td>257</td><td>0.001</td></tr><tr><td>Globus palidum int. (R)</td><td>24, -13, 4</td><td>2.58</td><td>36</td><td>0.005</td></tr><tr><td colspan="5">Tremor L (negative contrast)</td></tr><tr><td>Putamen (L)</td><td>-30, -9, 12</td><td>3.22</td><td>123</td><td>0.001</td></tr><tr><td>Putamen (R)</td><td>22, -3, 15</td><td>2.80</td><td>67</td><td>0.003</td></tr><tr><td colspan="5">Tremor R (negative contrast)</td></tr><tr><td>Vermis/cerebellum (L), p. IV</td><td>-12, -43, -5</td><td>2.82</td><td>33</td><td>0.002</td></tr><tr><td>Substantia nigra (R)</td><td>10, -20, -6</td><td>2.78</td><td>76</td><td>0.003</td></tr></tbody></table>

<sup>a</sup> Shown are the x, y, z Talairach coordinates (see Methods), the peak Z score, the cluster size, and the corresponding P value. All the correlations shown concern structures that were part of our a priori hypothesis (hypothesis-driven cutoff, P ≤ 0.005, uncorrected). See Methods for the approach used.

CMRglc in PD to compare with our findings. As detailed in the Introduction, Ohye *et al.* (1991) reported higher rCMRglc in the basal ganglia in tremor-type PD patients, and Antonini and co-workers (1998) reported increased metabolic activity in a topographic profile comprising the lenticular nucleus, thalamus, lateral premotor cortex, and pons with more severe tremor. Our findings concerning the putamen would therefore be consistent with these earlier studies. However, the negative direction of this correlation in our study would be inconsistent with these earlier reports. Thus, Antonini *et al.* (1998) reported increased relative metabolic activity in the lenticular nucleus with more severe tremor. However, the weight of the lenticular nucleus in Antonini and co-workers' network was less marked than that of the cortical and thalamic regions, and their lenticular ROI included both the putamen and the globus pallidus. One major difference between Antonini and colleagues' study and ours is that these authors studied their subjects in the OFF state whereas we studied ours in the ON state, which as discussed above may well have influenced the direction of the correlation with CMRglc. For instance, the lack of significant correlation between tremor and thalamic metabolism in our study may relate to this design (Broussolle *et al.*, 1993; Berding *et al.*, 2001). Clearly, assessing the correlation between FDG-PET and motor scores in both the ON and the OFF states would be helpful in addressing these issues, and would perhaps shed interesting new light on the intricate synaptic dysfunction of the basal ganglia and thalamus in PD.

The correlation between tremor sum scores and cerebellar vermis nCMRglc was also negative, such that the more severe the tremor the lower the vermian

metabolism. In their study, Antonini *et al.* (1998) found no significant difference in cerebellar nCMRglc between PD patients with and without resting tremor, and no participation of the cerebellum in the topographic profile discriminating these two groups. However, the vermis was not sampled in their cerebellar ROI. PET activation studies indicate that cerebellar overactivity is implicated in PD tremor. Duffau *et al.* (1996) reported an increased rCBF in the cerebellar vermis when comparing tremulous PD patients while under and while off L-DOPA. Studies in patients implanted in the nucleus ventralis intermedius of the thalamus have consistently observed increases in cerebellar vermis blood flow during tremor and decreases with tremor arrest (Parker *et al.*, 1992; Deiber *et al.*, 1993; Davis *et al.*, 1997). Recent views posit that by preventing the rest tremor from spilling over into voluntary movement, the cerebellum may have a compensatory rather than a causal role with respect to rest tremor in PD (Deuschl *et al.* 1999). Thus, the observed tremor-related overactivity may be related to the cerebellum actively limiting the rhythmical activity produced by the basal ganglia (Deiber *et al.*, 1993). Overactivity of the cerebellar vermis is also observed in essential tremor (Colebatch *et al.*, 1990; Jenkins *et al.*, 1993; Wills *et al.*, 1995), the pathophysiology of which partly overlaps that of resting tremor. Although the correlation between tremor scores and vermis nCMRglc found here is consistent with this literature, the negative direction of this correlation is, however, difficult to explain, but may have to do with the resting-state type of measurement and also with the fact that our patients were studied in the ON state.
We also found a significant correlation between right tremor scores and right substantia nigra nCMRGlc (see Fig. 5). This has not previously been documented in PD. The direction of the correlation, with tremor worse with decreasing CMRGlc, makes neurobiological sense, as it likely reflects greater loss of SNpc neurons. Why it showed up only for right tremor and right SN is unclear, but all our patients had bilateral pathology.

## Overlap

One additional and striking finding in this study concerned the extensive overlap of inverse nCMRGlc correlations with tremor and bradykinesia scores in the bilateral putamen. Thus, overlapping portions of the putamen seem to be involved, but in opposite directions, in these two major clinical features of PD, pointing to the intricate pathophysiology of this disorder. Of note, this overlap was computed for each clinical variable independently of the other, and thus does not reflect mere colinearity. As a matter of fact, and as expected based on classic clinical observation, there was only a weak trend of correlation between tremor and bradykinesia scores in this sample. On a pathophysiological viewpoint, imaging is not suited to assess whether this overlap represents the same neurons having inverse effects on tremor and bradykinesia or distinct cell populations, e.g., striosomes and matrix, being sampled in the same voxel. However, Obeso and co-workers' (2000) note that "the motor manifestations associated with depletion of DA in PD are mediated by specific alterations in the firing patterns of the motor loops" would be compatible with the former explanation.

## CONCLUSION

This study using voxel-based mapping in stable and uncomplicated PD patients studied in the ON state documents direct relationships between cerebral regions specifically affected in, and classic clinical features of, this neurodegenerative process. Overall, the findings are entirely consistent with, and further highlight the role of, the striatocortical and cerebellocortical loops in the genesis of bradykinesia and tremor in PD. However, the interpretation of the direction of some correlations is not straightforward and raises interesting and challenging issues, especially regarding how DA medication may modulate the relationship between resting-state CMRGlc and motor changes. As the concept of functional motor circuitry is still evolving since the seminal description by Alexander and Crutcher (1990), care is mandatory when attempting to address the central role of the DA-depleted "motor" basal ganglia in PD (Obeso et al., 2000).

## ACKNOWLEDGMENTS

We are grateful to the Association France-Parkinson, the Association pour la Neuropsychopharmacologie, and the Region Basse-Normandie for providing the studentship for the first author; Professor G. Defer for his support; J-B. Poline for his helpful advice on SPM; and B. Landeau for help with the illustrations.

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