Influence of Motor Activity on Striatal Dopamine Release: A Study Using Iodobenzamide and SPECT

NeuroImage 10, 261–268 (1999) Article ID nimg.1999.0461, available online at http://www.idealibrary.com on

Influence of Motor Activity on Striatal Dopamine Release: A Study Using Iodobenzamide and SPECT1 R. Larisch, B. Schommartz, H. Vosberg, and H.-W. Mu¨ller-Ga¨rtner Department of Nuclear Medicine, Heinrich-Heine-University, Moorenstrasse 5, 40225 Du¨sseldorf, Germany Received October 6, 1998

Pharmacologically induced dopamine release can influence the postsynaptic receptor binding of dopaminergic radioligands. This effect has recently been described using in vivo imaging methods and has been attributed to competition of radiotracers with the endogenous ligand. The present study examines the effect of a motor activation task on dopamine release and the consequences of this release on the binding of the selective D2 receptor ligand 123I-iodobenzamide (IBZM) to striatal dopamine D2 receptors. Eight subjects were asked to write a text beginning immediately before IBZM injection and continuing for 30 min thereafter. Eighteen other subjects remained in a supine resting state during this period and served as a control group. All subjects were right handed. We hypothesized that the writing task would lead to an increase of dopamine release. The increased competition of the endogenous ligand with IBZM should lead to a decreased postsynaptic IBZM binding in the experimental group. Images were acquired and reconstructed identically and anatomically normalized to a computerized brain atlas. Regions of interest were drawn covering the striatum and three different reference regions. Ratios of striatal-to-reference-tissue radioactivity accumulation were calculated as semi-quantitative estimates of D2 receptor binding potential. This decreased bilaterally, although right-sided significantly more than left, regardless of the choice of reference region. These data show that writing with the right hand compared to a supine resting state leads to a decrease of striatal IBZM accumulation. According to our primary hypothesis this reflects dopamine release. r 1999 Academic Press

INTRODUCTION Positron-emitting ligands such as [ 11C]raclopride (Ehrin et al., 1985; Farde et al., 1985), [ 18F]spiperone (Arnett et al., 1985), and [ 18F]methyl-benperidol (Moer1 Supported by a grant from the ‘‘Deutsche Forschungsgemeinschaft’’ DFG (LA 1003/2-1).

lein et al., 1992) have been developed for the examination of dopamine D2 receptors in vivo using PET. For clinical use, an iodinated benzamide, [ 123I]iodobenzamide (IBZM), has become available for SPECT imaging (Kung et al., 1989). These ligands can be used to study postsynaptic dopamine D2 receptors in normal volunteers and in patients with specific disease conditions. The status of the receptors has been investigated in PET studies of specific neuropsychiatric disorders, including depression (D’haenen and Bossuyt, 1994), schizophrenia (Wong et al., 1986), and Parkinson’s disease (Antonini et al., 1994; Cordes et al., 1993; Schwarz et al., 1993). However, in addition to alterations in the receptor density, the in vivo binding of dopamine D2 receptor ligands can be sensitive to changes in the extracellular concentration of dopamine. For this reason, several studies investigated the influence of pharmacologically induced modulation of dopamine release on postsynaptic receptors: Ginovart et al. tested the effect of reserpine on [ 11C]raclopride binding in monkey brain. The authors found that reserpine-induced dopamine depletion leads to a marked increase in radioligand binding, which was still detectable 20 days after treatment (Ginovart et al., 1997). Conversely, Laruelle et al. measured striatal IBZM binding using SPECT imaging before and after damphetamine challenge. They found that amphetamineinduced dopamine release leads to a decrease in D2 receptor availability for IBZM (Laruelle et al., 1995). Finally, Dewey et al. modulated striatal dopamine by manipulating the serotonergic system with several drugs using in vivo microdialysis in conjunction with PET as imaging tool (Dewey et al., 1995). Briefly, they found that the serotonin 5HT2 receptor antagonist altanserin increased extracellular striatal dopamine concentrations and consecutively decreased striatal raclopride binding. Conversely, the serotonin reuptake inhibitor citalopram decreased extracellular striatal dopamine concentrations and thereby increased raclopride binding. Postmortem studies of Parkinson’s disease have revealed the importance of an intact nigrostriatal dopa-

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mine pathway for the control of movement suggesting that—similar to the pharmacological treatments described above—voluntary movement might effect dopamine release. This hypothesis is supported by animal studies (Schwarting, 1997). Moreover, a first in vivo indication comes from a recent PET study in humans: playing a video game leads to a decrease of striatal [ 11C]raclopride binding (Koepp et al., 1998). The present study assesses dopamine release by means of postsynaptic striatal dopamine D2 receptor binding induced by a writing task using IBZM and SPECT. Our hypothesis is that writing should result in a lowered IBZM binding because of competition by a rising synaptic concentration of endogenous dopamine. MATERIALS AND METHODS In an ongoing prospective study, we have so far investigated 26 persons, 18 of whom were randomly assigned to the control group. Another 8 were randomly related to the experimental group and had to perform a writing paradigm (writers). We decided to build up a larger control group first because dopamine D2 receptor binding is known to be age dependent and might also be influenced by gender. With this larger control group we were able to correct better for the confounding effect of age. All subjects had a history of malignant melanoma and underwent IBZM scintigraphy for clinical reasons (Larisch et al., 1998; Maffioli et al., 1994). Brain metastases were excluded by morphological imaging. Neurological and psychiatric diseases were excluded by history and physical examination. Each patient gave written informed consent to the study. The study protocol was approved by the Ethical Committee of the University of Du¨sseldorf. The mean age of the writers was 51 ⫾ 12 years (mean ⫾ SD) with a range from 38 to 72 years, six being males and two females. The control group was aged comparably (59 ⫾ 15 years, range: 32 to 87 years). In this group nine subjects were female and nine male. All subjects were right handed according to the criteria of Annett (1970). Subjects of the test group were asked to write a poem in German language (Heinrich Heine: ‘‘Deutschland— ein Winterma¨rchen’’) beginning immediately before injection and continuing for 30 min thereafter. They were told to write as fast as possible without stopping to correct orthographic errors. Nonwriters rested in a supine state with ears and eyes uncovered during this period. From 30 to 90 min after injection all subjects remained in a quiet room and were asked to relax. IBZM SPECT was performed in each subject 90 min after injection. Details of the data acquisition and reconstruction methodology are published elsewhere (Larisch et al., 1997). Briefly, all subjects received about 185 MBq of

IBZM intravenously. Data acquisition started 90 min after injection using a double-headed SPECT camera. The acquisition time was 30 min. All images were reconstructed identically using filtered backprojection and were normalized according to the standard anatomy of a computerized brain atlas (CBA) (Greitz et al., 1991). The CBA resliced each brain into 15 consecutive transversal slices of 9-mm thickness. The frontal cortex region of interest (ROI), which was used as reference region, had a size of 46 cm3 and was predefined according to the atlas anatomical database. Additional reference regions of comparable sizes were defined in the parietal cortex and the cerebellum in the same way. The striatum is known to vary considerably across different subjects due to individual differences in ventricular size. Therefore the automatic ROI definition by the standardized atlas is inaccurate for this structure and we decided to manually draw the striatum ROI. To minimize observer inferences we used a standard rectangular ROI covering a volume of 10 cm3 on slice seven representing the center of the striatum (Fig. 1). Striatal IBZM binding was normalized to the frontal cortex. The SPECT data were analyzed blindly in this way. For further analysis the striatum-to-frontal-cortex ratio was referred to as IBZM binding. Data are given as mean ⫾ standard deviation (mean ⫾ SD) unless otherwise stated. P values ⬍ 0.05 were regarded as biologically relevant. Statistical analysis of changes in dopamine D2 receptors between the experimental groups was performed using Student’s t test, age effects were tested using standard linear correlation analysis. RESULTS In the control group, the mean striatum-to-frontal cortex IBZM uptake ratio ⫾ standard deviation was 1.46 ⫾ 0.1 on the right and 1.44 ⫾ 0.09 on the left side (P ⫽ 0.1; paired t test). In the writers, the ratios were 1.43 ⫾ 0.09 for both sides. First, we evaluated age and gender as possible confounding factors of influence on our results: striatal IBZM binding was age-dependent in the control group as well as in the writers. In the controls a linear regression analysis showed a decline of 4.5% per decade for the right (r ⫽ ⫺0.73; P ⬍ 0.001) and 3.6% per decade for the left side (r ⫽ ⫺0.64; P ⫽ 0.004; Fig. 1). The writers showed a decline of 7% per decade on the right (r ⫽ ⫺0.92; P ⫽ 0.001) and 5.1% on the left side (r ⫽ ⫺0.71; P ⫽ 0.05). The IBZM binding values did not differ in men and women (right, P ⫽ 0.38; left, P ⫽ 0.92, t test). Based on these findings, we performed a multiple regression analysis on all subjects with IBZM binding ratio as the dependent variable and age and group affiliation (writer vs nonwriter) as independent vari-

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FIG. 1. Example of a reconstructed image acquired 90 to 120 min after injection of 185 MBq IBZM showing accumulation of the tracer in the striatum. The image is anatomically normalized using a computerized brain atlas, which delineates the outlines. The atlas database automatically defines the ROI of the reference regions (frontal cortex, parietal cortex, and striatum). However, because of the large variations of the position of the human striatum, this structure needed to be delineated ‘by hand’ using standard rectangular ROI as demonstrated here. The position of the ROI but not the size was adjusted individually for each subject.

ables. Since we found no consistent evidence of a gender dependency of dopamine D2 receptors in the literature as well as in our data, we decided not to include gender as confounding factor in the further analysis. In this linear model, age (P ⬍ 0.001) and group affiliation

(P ⫽ 0.01) contributed significantly to predict the right striatal IBZM binding, accounting for 61% of the total variance. For the left side the influence of group affiliation was insignificant (P ⫽ 0.15), whereas age remained highly predictive (P ⬍ 0.001). Together, both

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factors explained only 43% of the total variance of left striatal IBZM binding. Because the differences between the two experimental groups is the main finding of the study we tried to confirm it using another statistical method: we corrected the data for the age effect. For this, we used the slope of the regression line of striatal IBZM accumulation with age in the control group. The corrected and uncorrected data of both groups are presented in Table 1. After age correction, the writers still showed a correlation of IBZM binding and age on the right side, which was borderline significant (r ⫽ ⫺0.68; P ⫽ 0.06), indicating that on this side the writing task has a greater effect in elderly subjects than in younger ones. The left sided correlation coefficient of IBZM accumulation and age was insignificant after age correction (r ⫽ ⫺0.32; P ⫽ 0.45). After correction of the data for the age effect, the mean IBZM binding values were lower in the writers than in the nonwriters (Fig. 2). This difference reached significance on the right (P ⫽ 0.01, t test) but not on the left side (P ⫽ 0.17). We additionally performed a more conservative nonparametric test for this analysis. However, Mann–Whitney rank sum test reproduced this finding (right, P ⫽ 0.004; left, P ⫽ 0.29), confirming the results of the multiple regression analysis. To exclude an influence of the reference region on the calculated IBZM binding ratios we repeated the above described analysis using a parietal and a cerebellar

reference region instead of the frontal one (Table 2). Using the parietal cortex as reference, the age corrected striatal IBZM binding decreased from 1.59 ⫾ 0.11 and 1.57 ⫾ 0.10 on the right and left side of the control group to 1.52 ⫾ 0.12 on both sides of the writers. This reached significance on both sides (right, P ⫽ 0.006; left, P ⫽ 0.049, t test). Finally, using the cerebellum as reference, the control’s respective IBZM binding values decreased from 1.71 ⫾ 0.11 and 1.69 ⫾ 0.12 to 1.57 ⫾ 0.13 and 1.58 ⫾ 0.14 in the writers. This also reached significance right with a clear trend toward significance left sided (right, P ⫽ 0.01; left, P ⫽ 0.07). DISCUSSION The present study shows the effect of writing on IBZM binding to striatal dopamine D2 receptors: the IBZM binding in the striatum was lower in writers than in nonwriters. This decrease of postsynaptic receptor binding reached significance in all tests on the right side of the brain and approached significance in most cases on the left side. This finding is in good agreement with our a priori hypothesis that motor activity should be linked to increased endogenous dopamine release and that IBZM binding should be lowered in writers because of competition between increased dopamine and IBZM in the synaptic cleft. The theory of movement-dependent dopamine release can also explain the different age dependency of

TABLE 1 Striatum-to-Frontal-Cortex Ratios of IBZM Accumulation in 18 Control Persons and 8 Subjects Who Performed a Writing Task (Writers) Controls

Writers

Age

Right

Rightcorr

Left

Leftcorr

Age

Right

Rightcorr

Left

Leftcorr

32 82 55 52 70 49 87 63 60 67 66 50 77 49 70 44 32 60

1.69 1.34 1.50 1.47 1.41 1.52 1.36 1.47 1.60 1.41 1.38 1.54 1.41 1.48 1.40 1.41 1.55 1.33

1.56 1.44 1.47 1.43 1.46 1.47 1.48 1.48 1.60 1.45 1.41 1.50 1.49 1.43 1.44 1.34 1.42 1.33

1.67 1.29 1.44 1.43 1.44 1.47 1.36 1.39 1.52 1.39 1.35 1.50 1.46 1.54 1.46 1.42 1.46 1.33

1.57 1.37 1.42 1.40 1.48 1.43 1.45 1.40 1.52 1.42 1.37 1.47 1.52 1.50 1.49 1.36 1.36 1.33

40 72 51 58 61 44 43 38

1.50 1.33 1.44 1.35 1.29 1.50 1.49 1.52

1.41 1.38 1.40 1.34 1.30 1.43 1.42 1.42

1.51 1.42 1.41 1.36 1.27 1.44 1.49 1.53

1.44 1.46 1.38 1.35 1.27 1.38 1.43 1.46

Note. The age of each subject is given in the left column. Ratios are age-dependent in both groups. In the controls they decline with 4.5% per decade on the right and 3.6% on the left side, which is the reason for performing an age-correction on the original data. For this, the slope of the regression line was added for each decade above 60 years (mean age of the controls) and subtracted for each decade below this age.

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FIG. 2. Differences of right and left striatal IBZM accumulation normalized to the frontal cortex in controls and writers. The line inside the gray boxes is the median. The boxes represent the 25–75% interval. The whiskers show the 5–95% interval. IBZM accumulation in the right striatum (two left columns) was significantly higher in the controls than in the writers (P ⫽ 0.01, t test; and P ⫽ 0.004, Mann–Whitney rank sum test). The respective differences for the left side (two right columns) did not reach significance.

writers and nonwriters. As known from earlier studies the number of D2 receptors decrease with age (Antonini et al., 1993; Crow et al., 1984; Wang et al., 1995). There is also an age-related loss of nigrostriatal fibers (Emborg et al., 1998) and a consequent decrease of the tissue level of striatal dopamine (Kish et al., 1992). Thus, aged subjects possess fewer striatal D2 receptors, whereas the amount of dopamine per synapse remains relatively stable leading to an increased competition of IBZM and dopamine for a fewer number of binding sites in the elderly. Consequently, the decrease in IBZM binding with age is stronger in writers than in nonwriters. Therefore, the difference in regression of D2 receptor binding with age in writers and controls further supports our hypothesis of movement-dependent dopamine release as reason for the lower IBZM binding in the writers. It might be objected that the present alterations in IBZM ratio could be attributed to changes in cerebral blood flow. These blood flow changes might lead to a different IBZM delivery to the striatum and consequently to the observed differences between writers

and nonwriters. The earlier activation studies of skilled hand movements using 133Xe inhalation and single photon emission tomography did not find significant blood flow effects in the basal ganglia (Decety et al., 1988; Lauritzen et al., 1981). However, this might be attributed to methodological problems. An early PET study of ballistic finger movements found increases of regional blood flow in globus pallidus of 30% contralaterally and 15% ipsilaterally (Roland et al., 1982). In caudate nucleus and putamen bilateral blood flow increases of 11–15% were observed. In supplementary motor area regional blood flow increased by 30%. A more recent study using functional magnetic resonance imaging was specifically dedicated to striatal signal intensity changes following rapid supination and pronation of the hand (Bucher et al., 1995). The authors observed increases of the magnetic resonance signal intensity varying from 3.1 to 23.4% during activation. All 12 subjects showed signal intensity increases in the globus pallidus internus; 7 in globus pallidus externus and 10 in putamen. Three of the 12 subjects showed bilateral activations, whereas the others showed pre-

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TABLE 2 Striatum-to-Parietal-Cortex and Striatum-to-Cerebellum Ratios of IBZM Accumulation Controls Parietal

Writers

Cerebellum

Parietal

Cerebellum

Right

Left

Right

Left

Right

Left

Right

Left

1.73 1.55 1.69 1.58 1.62 1.58 1.63 1.57 1.72 1.56 1.52 1.57 1.59 1.49 1.57 1.40 1.57 1.54

1.74 1.48 1.63 1.54 1.64 1.53 1.60 1.48 1.63 1.53 1.48 1.54 1.62 1.56 1.63 1.43 1.51 1.55

1.75 1.67 1.63 1.59 1.73 1.71 1.55 1.64 1.87 1.72 1.86 1.93 1.78 1.54 1.80 1.69 1.63 1.65

1.76 1.60 1.57 1.55 1.75 1.66 1.52 1.55 1.77 1.69 1.81 1.90 1.82 1.62 1.86 1.72 1.56 1.66

1.51 1.45 1.46 1.49 1.30 1.57 1.55 1.51

1.54 1.54 1.43 1.50 1.27 1.52 1.56 1.55

1.59 1.58 1.58 1.60 1.27 1.69 1.62 1.65

1.63 1.67 1.55 1.61 1.24 1.64 1.63 1.70

Note. All data are age corrected as described in the legend to Table 1.

dominantly signal intensity increases in the striatum contralateral to the activated hand. Thus, motor activation-dependent blood flow increases of basal ganglia are generally lower than those in cortical areas but might be found during writing. They should occur in the left striatum or bilaterally. However, even if blood flow would be increased in writers, this would not explain decreased IBZM accumulation. Thus, we conclude that striatal blood flow changes due to the writing paradigm are unlikely to explain our results. Another constraint could be that the blood flow in the reference region could be influenced by the writing task. Indeed, an increase of IBZM delivery via perfusion in a reference region due to writing could explain lowered ratios of striatum-to-reference-region. However, we introduced three different reference regions and our data remained significant for all of them. Moreover, the highest levels of significance were reached using the parietal cortex as reference, which is the one structure where the writing paradigm should have the least effect. Therefore, it is unlikely that the choice of reference region is responsible for the decrease of IBZM binding in the writers. A further argument against our interpretation of the data could be that IBZM binding is not influenced in first order by the amount of synaptic dopamine but rather by the number and affinity of postsynaptic D2 receptors. The kinetics of these sites could change during motor activity. However, receptor down regula-

tion is not likely to happen within minutes of time. Moreover, this postsynaptic effect is a consequence of a presynaptic mechanism, which is most likely dopamine release into the synaptic cleft. Therefore, even if the postsynaptic receptor kinetics might change during the experiment, according to this view, the decrease of IBZM binding following writing would still be due to dopamine release. The assessment of dopamine release with IBZM is already investigated by Laruelle et al. using a bolus plus constant infusion administration schedule and SPECT (Laruelle et al., 1995). The authors could demonstrate the effect of amphetamine on human endogenous dopamine release. Other studies demonstrated the possibility of measuring pharmacologically induced dopamine release using [11C]-raclopride (Dewey et al., 1993) or [18F]-N-methyl-spiroperidol and PET (Dewey et al., 1991). In these studies, compartmental analysis of the dynamic time-activity curves was carried out in conjunction with cerebral microdialysis for the detection of endogenous compounds. We contend that the present use of a simple ratio method is sufficient to detect effects of a motor task on dopamine release in human basal ganglia. The decrease of IBZM binding effected by our writing task was about 15% on the right and 9% on the left side. These values are similar to the data presented by Laruelle (15%), Farde (10%), or Volkow (23%) (Farde et al., 1992; Laruelle et al., 1995; Volkow et al., 1994). Dopamine release as a consequence of behavior has also been examined recently (Koepp et al., 1998). D2 receptors were determined using [ 11C]raclopride and PET twice. During the first 50 min of one examination subjects had to play a video game. To succeed in the game and to get a monetary incentive they had to navigate a tank that was visible on a computer screen through a battle field using a mouse. During the second examination subjects looked at an empty screen. The authors differentiated between ventral and dorsal striatum and found a 6.1% (right dorsal) to 13.9% (right ventral) decrease of raclopride binding potential in the video condition compared to the control condition. The respective values for the left side were 8.9% (dorsal) and 11.8% (ventral). The video game task involved several different brain functions, among them motor activity, visual attention, working memory, motivation, and reward. At least the first three of them were also mandatory for our writing task. However, motivation and reward were clearly less important for writing a text. In particular, because our subjects received no monetary incentive. The main finding of the study of Koepp and colleagues is a bilateral striatal dopamine release, whereas we found a dominance of the right side. The difference between the two tasks might explain the differences in the results between the two studies. High motivation could result in a bilateral

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dopamine release in the ventral limbic striatum, which is predominant in the results of the study of Koepp et al. In fact, it has been shown that dopamine release occurs bilaterally as a consequence of motivational behavior in electrophysiological studies (Schultz et al., 1992, 1993, 1997). Right-sided motor activity is the main stimulus in our investigation and lead to an ipsilateral more than contralateral dopamine release. Unilateral lesioning of the nigrostriatal pathway in rats leads to ipsiversive turning after amphetamine challenge (Ungerstedt, 1968). This is interpreted as a relative decrease of dopaminergic neurotransmission on the lesioned side leading to movement disorder on the contralateral side. Thus, unequal dopaminergic stimulation after striatal lesioning results in an asymmetrical output with dominance of the side of the body ipsilateral to the lesioned striatum. However, it does not follow necessarily from these experiments that voluntary movement of a hand involves only contralateral striatal dopamine release. Several studies have addressed the question whether unilateral dopaminergic lesions affect ipsilateral or contralateral paw usage in rodents. A detailed review of the literature is given by Schwarting and Huston (1996). In summary, after unilateral striatal dopamine depletion the motoric deficits are generally more pronounced on the contralateral side. However, when postural adjustments are required deficits occur also ipsilaterally. Our forced writing task in an upright sitting position clearly requires postural adjustments of head and upper extremities. This might be an explanation for our finding of bilateral but mainly right-sided dopamine release as a consequence of writing. Apart from the locomotion involved in our paradigm, the reading of the poem itself might induce dopamine release. Therefore, our findings cannot exclusively be attributed to motor activity but might be due to additional cognitive processes. We try to shed light on this point in a future study. We conclude that the examination of neurotransmitter release is possible using standard nuclear medicine methods. Studies of this parameter following neuropsychological tasks can lead to a better understanding of molecular correlates of behavior. Further studies of the dopaminergic system should examine motor activity and motivational effects more specifically. Benzamides like IBZM or raclopride are ideal for this kind of examination because their receptor binding properties seem to be sensitive for the presence or absence of synaptic dopamine. The examination of other receptor-transmitter systems should be possible using low-affinity radioligands. REFERENCES Annett, M. 1970. Left, Right, Hand and Brain: The Right Shift Theory. Antonini, A., Leenders, K. L., Reist, H., Thomann, R., Beer, H. F., and Locher, J. T. 1993. Effect of age on D2 dopamine receptors in

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