Pswhiatry Research: Neuroimaging, 55: 193-203 Elsevier

193

Mark S. George, Mary M. Robertson, Durval C. Costa, Peter J. Eli. Michael R. Trimble, Lyn Pilowsky, and N.P.L.G. Varhoeff

Abstract. A large body of evidence suggests that abnormal dopaminergic activity is present in Gitles de la Tourette Syndrome (GTS). To investigate whether dopa- mine dysregulation involving the D,/D, receptor occurs in GTS, we performed single slice dynamic single photon emission computed tomography (SPECT) with l%odo-6-methoxybenzamide (Q3I-IBZM) in 15 GTS patients (eight unmedicated) and six healthy volunteers. After intravenous administration of 5 mCi (185 MB@ of 1 WIBZM, dynamic SPECT (5 minutes per slice) studies were performed at the level of the basal ganglia for 55 minutes. The mean activity per pixel in the basal ganglia was compared with the mean activity per pixel in the visual cortex. Z!n- medicated GTS patients showed no differences from control subjects. However. GTS patients taking D, blocking medications had significantly decreased 12+ IBZM binding compared with control subjects in both the right and left basal ganglia. Thus, D2/ D, receptor availability, as measured by IWIBZM SPECT, is not abnormal in GTS.

Key Words. Single photon emission computed tomography, neuroleptics, ~~3iodo-6-metho~ybenz~ide, tics.

Gilles de la Tourette Syndrome (GTS) is a movement disorder characterized by chronic motor and vocal tics (Robertson, 1989). The anatomical location, frequency, complexity, and severity of the tics change over time, and the onset of the disorder characteristically occurs before the age of I4 years (American Psychiatric Associa- tion, 1987; Bruun, 1988). Although the exact prevalence of CTS is unknown, a currently accepted figure is 0.5 per thousand (approximately 110,ooO patients in the United States and 27,500 in the United Kingdom) (Bruun, 1988), but even this may prove to be an underestimate. GTS is found worldwide and in atl cultures, racial

Mark S. George, M.D.. is currently Senior Staff Fellow, Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD. At the time this work was done, Dr. George was Visiting Research Fellow, Department of Clinical Neurology, Institute of Neurology, Queen Square, London, England. He was also Neuropsychiatry Fellow. Department of Psychiatry and Behavioral Sciences. Medical University of South Carolina, Charleston, SC. Mary M. Robertson, M.D., F.R.C.Psych., is Consultant, Department of Psychiatry, University College London and Middlesex School of Medicine (UCMSM). London. Durvai C. Costa, M.D.. is Senior Lecturer, and Peter J. Eli, M.D., Ph.D.. is Professor of Nuclear Medicine. Institute of Nuclear Medicine, London. Michael R. Trimble, F.R.C.P.. F.R,C.Psych., is Raymond Way Reader in Behaviourat Neurology and Consultant in Psychological Medicine, Raymond Way Neuropsychiatry Research Group, Department of Clinical Neurology, Institute of Neurology. Queen Square, London. Lyn Pilowsky, M.R.C.Psych., is Lecturer, Institute of Psychiatry, DeCrespigny Park. London. N.P.L.G. Verhoeff, M.D., is Lecturer, Cygne B.V., Technical IJniversity, Eindhoven. The Netherlands. (Reprint requests to Dr. M.S. George, NIMH, Bldg. 10, Room 3N212.9000 Rockville Pike. Bethesda. MD 20892, USA.)

0365-1785 3943’$07,00 @ 1994 Elsevier Science Ireland Ltd

groups, and social classes (Rohert5on. I9W). It occurs three or tour t~rnes more col~rn~~nly in males than in females.

The etiology of GTS is now generally thought of as being biological, rather than psychodynamic. although stress exacerbates tics. Some authors have suggested an

autosomal dominant gene involving tics. GTS, and obsessive-compuIsive disorder (GCD) (Pauls et al., 1986; Robertson, 1989). The neurochemical basis for GTS is. as yet, not known, with several putative neurotransmitter abnormalit& alread>

reported (Caine et al., 198X; Singer cl al.. 1990). However, the neurotransmitter dopamine has received the most attention, mainly because dopaminc-blocking agents (e.g.? haloperidol) reduce GTS symptoms, ‘while dopaminergic stimulants (e.g., pemoline, methylphenidate) worsen tics and related behavior. There are man\ potential steps at which dopamine dysfunction might occur in GTS (e.g.. over- production, decreased catabolism, abnormal receptor binding, heightened post- receptor signal) (Singer et al., 199 I). Genetic studies, however, have faiied to find linkage to the D, or I): receptor (Gelernter et al., 1990).

To investigate the possibility of abnormal D2 receptor binding or availability-, we used brain-dedicated multidetector single photon emission computed tomography (SPECT) (George et al., 1991) and the recently developed DJD,-receptor ligand. ‘%odo+methoxybenzamide (“‘1-lBZMj (Kung et al., 1989, 1990) to examine DZi I),-receptor activity in CiTS patients and control subjects.

Methods

Subjects. GTS subjects were recruited t’rom the Gil& de la Tourette Syndrome Clinic at The National Hospitals for Neurology and Neurosurgery, Queen Square, London. U.K. The referral pattern and demographic makeup of the GTS clinic has been previously described (Robertson et al., 1988; Robertson. 1989). Approximately one to two new GTS patients are evaluated per week from throughout the U.K., with a referral base of more than 56 miliion. Subjects were initially examined by a neucopsychiatrist (M.M.R.) to ascertain the diagnosis of GTS according to DSM-III-R criteria (Table 1) and then confirmed by another neurologist: psychiatrist (M.S.G.) before study entry. Additional measures included the National Hospital Tourette Interview and a specially chosen battery of standardized psychi- atric rating scales to measure specific aspects of psychopathology (Robertson et al.. 1988: Robertson. 1989). The mean duration of illness was IO years (SD = 9X), with a mean tic severity of 65 on the Yale Global Tic Severity Scale (Leckman et al., 1989). Exciusionar> criteria for both patients and volunteers included hepatic, renal or cardiac disease. pregnancy. seizure disorder, mental retardation, past history of cocaine or stimulant abuse. encephalitis, exposure to methylphen~date. or the presence of depression or severe psychiatric illnesses (other than OCD or GTS in the case of the patients),

Healthy volunteers were recruited from hospital staff at the Institute of Psychiatry using the inclusion and exclusionary criteria defined above. This research was approved by the ethics committees of The National Hospitals for Nervous Diseases, The Middiesex Hospital. and ARSAC (the U.K. regional radiation safety committee). informed written consent aa\ obtained from each individual.

Procedures. Scanning was done using a brain-dedicated single-slice tomograph. the Strichman Medical Equipment (SME) 810 Brain Tomograph, at the Institute of Nuclear Medicine (UCMSM). Subjects were placed supine on the SME 810 couch. The orbitomeatal line (OM line) was visually aligned with the gantry to obtain OM parallel slices. Dynamic SPECT was performed at the level of the OM line -i-- 30-40 mm. Subjects were instructed to

195

Table 1. Subject data

Subject Age Medication # (years) Sex (time since last taken) OCD ADHD HanUedness

1 27 2 45 3 29 4 10 5 15 6 31 7 12 8 15

Medicated mean 23

9 47

10 27

11 14 12 38 13 12 14 16 15 14

Medicated mean 24

Control mean 30

F Haloperidol, 3 months F Sulpiride, 4 months M Never medicated M Never medicated M Sulpiride, 3 months F Never medicated M Never medicated M Pimozide, 3 months

+ + + -

+ + +

513

M

(M/F) 612

Clomipramine, 100 mg/day Sulpiride, 800 mg/day Clomipramine, 100 mg/day Sulpiride, 80 mg/day Haloperidol, 5 mg/day Flupenthixol, 40 mg/4 wks Sulpiride, 200 mg/day Flupenthixol, 40 mg/2 wks Sulpiride, 400 mg/day Clomipramine, 30 mg/day

+

M -

- - + - c

6/l (M/F) 314

- R - A

R - R

R - R - R - R

O/8

- R

+ R

- R + R + R - R + R

413

412 VW 0 0 All R

Note. OCD = obsessive-compulsive disorder. ADHD = attention deficit hyperactivity disorder. F = female. M = male. R = right. L = left.

keep their eyes open and not to talk. After resting quietly for l-2 minutes, subjects were given an intravenous injection of W-IBZM through a 19-gauge needle in the right antecubital vein. The average dose of 5 mCi (185 MBq) was flushed through with 20 ml of saline. (r*rI-IBZM was supplied by Cygne B.V., University of Eindhoven, The Netherlands.) Binding of ;rrI- IBZM peaks 30-40 minutes after the injection and has a linear washout rate, resulting in a relatively stable target-to-background ratio of activity for up to 2 hours after the injection (Kung et al., 1989, 1990; Costa et al., 1990; Brucke et al., 1991).

Scanning began immediately after the injection and continued for as long as the subjects could accept. Most subjects and volunteers tolerated at least 55 minutes of scanning, and thus the data analysis for this study is limited to 55 minutes. Acquisition time per slice was 5 minutes with a 1.5-minute interscan interval. The in-plane resolution of this system is 7-9 mm (full width at half maximum). The average slice thickness was 1.25 cm. Images were then reconstructed using SME software on an Apple Macintosh computer.

Image Analysis. Regions of interest (ROIs) were drawn with a mouse around the entire frontal lobe, entire visual cortex, and the right and left basal ganglia by a neurologist (MSG.) who was unaware of diagnosis at the time of the analysis. A template for the right and left basal ganglia was drawn around the 60-minute image with the 70% isocolor contour (Fig. I). Frontal lobe and visual cortex templates were drawn on the IO-minute image (blood flow/perfusion dependent distribution of 1*3I-IBZM) at the 40% isocolor contour. The same

Fig. 1. Transverse 1231-1BZM image at 60 minutes after injection with C( 3lor scale adjusted such that the 70% isocolor contour defines p bi asal ganglia definition

the eak

EM “jiodo-6-methoxybenramide 1 he 6%mriute image was used for optimal placement of the basal cj:

n of interest used for all subjects

197

templates were used for all scans, adjusted to fit optimally over the defined regions. This ROI sampling method has a 2.2% mean variation in the regions used.

Statistical Analysis. Ratios. Because numerous factors can affect the total count rate in a given patient (e.g.,

amount of ligand absorbed, ligand remaining in the syringe), basal ganglia to visual cortex (BG/VC) and basal ganglia to frontal cortex (BG/FC) ratios were used to express relative i231-IBZM regional activity and produce a qualitative index of D, receptor availability. The regions used included both hemispheres.

Similar results emerged when basal ganglia to frontal cortex (BG/FC) ratios were used. However, some of the GTS patients in this study also participated in a SPECT blood flow study that found increased right frontal blood flow in GTS subjects compared with control subjects (George et al., 1992). Thus, to avoid possible confounds due to changes in frontal blood flow, we present only BGjVC ratios.

Relative binding curves. Mean BGjVC ratios for the left and right hemispheres were computed by group (control subjects, unmedicated and medicated GTS patients) for each time data point (from 0 to 55 minutes after injection). To produce a relative binding curve for ‘23I-IBZM, group right and left BGjVC ratios were expressed over time (Fig. 2). Group means of each BGjVC value at each time point were compared by two-way repeated measures analysis of variance (ANOVA) (3 groups X time) for each hemisphere, with post hoc Student- Newman-Keuls tests for significance.

Slopes of binding curves. The ANOVA cannot deal with missing data points, and thus 9/21 cases were rejected. These initial and late missing data points were due to patient movement, artifact, or the inability to tolerate 55 minutes of scanning (see Fig. 2). To test whether the results were erroneously influenced by the small number of subjects that entered the ANOVA, we used an additional method of data analysis. Each subject’s relative binding curve for each hemisphere from 0 to 55 minutes was plotted on a Macintosh computer with commercial software (Cricket Graph) which then computed a simple linear (first-degree polynomial) equation (y = mx + b) to fit each subject’s relative binding curve. Initially, we performed a hemisphere X group ANOVA to assess hemispheric differences. Then, for both the right and left hemispheres, the mean slopes for each group were compared by one-way ANOVA, with post hoc t tests (Student-Newman-Keuls procedure).

Fig. 2. 1231-IBZM binding curves of the right and left basal ganglia/visual cortex over time by groups (medicated GTS patients, unmedicated GTS patients, and control subjects)

1231-ISZM = 9odo-6-methoxybenzamide. GTS = Gilles de la Tourette’s Syndrome. For both the right and left basal ganglia, the medicated GTS group shows drfferences that became apparent at 20 minutes after Injection. The unmedicated group did not differ significantly from control subjects. The numbers immediately above a graphed point indicate where the number of subjects included in the group mean is less than the total stated on the right due to motion or artifact.

Results

Two-Way Repeated Measures ANOVA (3 Groups X Time). Within subjects (time effect). For both hemispheres, a significant time effecr

occurred, demonstrating significant binding of the ligand to receptors over tirnc

(n = 13; right: F= 27.72; c$#‘= 9.90; p < 0.001: left: F= 38.89; #= 9,90: /I r” 0.00 I 1. Between subjects (group effect). A significant between-sub,~ec~ group effect

was found in the right basal ganglia ( k’= 6.07; df”- 2, IO; p I= 0.019). This was due to a significant difference between normal control subjects and medicated GTS subjects (n = 13 total: 6 control subjects: mean BG; VC slope = I.3 1, SD = 0.1 I: 4 medicated CTS patients: mean BG/ VC slope = 1.12, SD = 0.03; 3 unmedicated GTS sub.jects: mean BG/ VC slope = I. 19, SD of 0.09; [’ < 0.05).

A significant between-subjects group effect was found. In the left basal ganglia ( F = 8.08: IY@= 2. 10: p =I 0.008). Post hoc tests revealed that this was due to significant differences between medicated GTS patients and control subjects, and between unmedicated GTS patients and control subjects (n = 13 total; 6 control subjects: mean BGjVC slope -z 1.37. SD = 0.10; 4 medicated GTS patients: mean BG,‘VC slope = I. 18. SD = 0.025; 3 unmedicated GTS patients: mean BG: VC slope = I .24, SD = 0.15; p cc: 0.05).

One-Way ANOVA of Uptake Slopes X Group. A group X hemisphere ANOVA revealed significant effects of group ( F = 8.9 I ; df= 2, 18; p =I. 0.002) and hemisphere ( F = 5.95: LEf’ = 1. 18; p I= 0.025), although there was no significant group >: hemisphere interaction. For both the right and the left basal ganglia, the medicated group had significantly lower slopes (relenting lower Dz/ D3 binding over time) than control subjects or unmedicated GTS patients on the basis of post hoc Student- Newman-Keuls tests. Other differences (i.e., between unmedicated GTS patients and control subjects) were not significant.

A significant between-group difference existed for the right and left BG/ VC mean sfopes. On the right, this difference ( F = 5.86; df= 2, 18; p = 0.0 1) was attributable to a si~nificantiy lower group mean slope (p < 0.05) in medicated GTS patients ( tt :=z 7; mean group slope = 0.001943, SD = 0.0048) than in control subjects ( PT =z 6. mean group slope = ~~0044, SD -= 0.0022), and between medicated GTS patients and unmedicated GTS patients (tz = 8, mean slope = 0,008388, SD = 0.0034). On the left. this significant difference ( I-= 10.45; L#‘= 2, 18: 17 = 0.001) was attributable, as it was on the right, to significant differences (12 < 0.05) between medicated GTS patients (II = 7. mean slope = 0.003 129, SD = 0.003087) and control subjects (?I-‘: h. mean slope = 0.0072, SD I: 0.002158) and between medicated GTS patients and unmedicated GTS patients (II =: 8, mean slope = 0.010450, SD = 0.003625).

More consistent results were found with the slopes method, which used a larger number of subjects, than with the repeated measures ANOVA.

Discussion

Dopamine Theory. There are several reasons for believing that dopamine may be involved in the pathophysiology of GTS. The main argument for dopamine’:,

199

involvement in GTS comes from observations of treatment effects. The brain dopamine neurotransmitter system acts through at least two different receptors, D, and Dz (Singer et al., 1991), although more are being identified and cloned. The affinities of neuroleptics for D, sites are closely correlated with the amelioration of psychotic and movement disorders (Singer et al., 1991). Thus, the D2 receptor could play a crucial role in GTS since the largest class of medications that successfully treat GTS are D, receptor antagonists such as haloperidol (Shapiro and Shapiro, 1982) pimozide (Golden, 1984; Colvin and Tankanow, 1985), and sulpiride (Robertson et al., 1990). Some GTS patients, however, do not benefit from neuroleptic medication (Robertson, 1989). It is therefore possible that responsiveness to dopamine (D2) antagonists may identify two distinct subgroups of GTS patients.

Another argument for the involvement of dopamine in GTS comes from the fact that dopaminergic agonists such as L-dopa (Sacks, 1982) and central nervous system (CNS) stimulants such as methylphenidate (Golden, 1984) have an adverse effect on GTS symptoms, while dopamine depletors such as tetrabenazine (Jankovic et al,, 1984) are associated with moderate improvement. The monoamine metabolite homo- vanillic acid has been found to be decreased in the cerebrospinal fluid of some GTS patients, although the methods involved have been criticized (Caine, 1985).

Neuroimaging in GTS, Several groups are currently using imaging techniques to investigate abnorma~ties in GTS, and their results suggest that the abnormalities involve both CNS function and structure. Robertson et al. (1988) reported 71 out of 73 patients with GTS to have normal findings on computed tomography (CT). Other studies have noted CT scan abnormalities in 16 GTS patients; only 18 out of 172 documented CT scans have been abnormal, and the abnormalities do not appear to be of direct etiological significance (Robertson, 1989). Recently, two separate studies have found reduced basal ganglia volumes in GTS patients compared with control subjects. Peterson et al. (1993) studied 14 adult GTS patients and found them to have decreased volume, as indicated by magnetic resonance imaging, in the left lenticular nuclei compared with findings in age-matched control subjects. In another MRI study, Singer et al. (1993) found that 37 GTS children had decreased volume in their left globus paliidus compared with their right, an asymmetry that was not present in 18 control subjects.

An initial study with positron emission tomography (PET) that used i*F-deoxy- glucose found abnormalities in five GTS patients compared with control subjects (Chase et al,, 1984). GTS patients showed a relatively close positive association between metabolism in the basal ganglia ~particularly the corpus striatum~ and metabolism throughout the cerebral cortex. Vocal tic severity varied inversely with glucose metabolism in the middle and inferior parts of the frontal lobes bilaterally, extending posteriorly from the frontal poles to the postcentral gyrus. Coprolalia, in contrast, was inversely correlated with hypometabolism in the left parasylvian region (Chase et al., 1984). In a more recent study that used a PET scanner with higher resolution and sensitivity, Chase et al. (1986) compared 12 untreated GTS patients with matched normal control subjects. At horizontal levels from 8.4-8.8 cm caudal to the vertex, nonnormalized glucose utilization rates were approximately 15Yc below control values in the region of the frontal cingulate and possibly insular cortex and in

the inferior corpus striatum (p Cc 0.01). Further studies by the same group (Braun et

al., 1991; Stoetter et al., 1991) have revealed focal neuroanatomical abnormalitie\ that primarily involve portions of the putamen and frontal and limbic cortices. In LI

recent SPECT study with technetium-99m-d,l-hexamethyl-propylene amine oxime as tracer, George et al. (1992) found elevated frontal cerebral blood flow in 20 unmedicated GTS patients compared with eight healthy volunteers. Finally, Singer

et al. (1992) failed to find differences in dopamine binding between GTS patients and control subjects in a PET study with “C-N-methylspiperone as the ligand.

Obsessive-compulsive disorder (OCDj is believed by some investigators to be genetically, phenomenologically, and probably neuroanatomically linked to GTS

(Pauls et al., 1986; Baxter, 1990; George, 1992). Studies of brain structure in OCD are conflicting, with some reporting decreased caudate volume in OCI>

(Luxembourg et al., 1988) and others not (Garber et al.. 1989; Kellner et al., 1991). Functional neuroimaging studies of OCD using ‘XF-deoxyglucose PET have

consistently revealed increased glucose metabolism in the caudate nuclei and orbital frontal lobes (Nordahl et al.. 1989; Swedo et al.. 1989; Baxter, 1990).

Interpretation of Results. As would be predicted, GTS patients taking dopamine- blocking medications displayed decreased ‘?‘I-IBZM activity in both basal ganglia.

consistent with blocked D?,’ D3 receptors. Activity was significantly lower than that in healthy control subjects and unmedicated GTS patients. Two separate methods oi data analysis corroborate this finding.

In addition, this study failed to demonstrate significant differences between unmedicated GTS patients and control subjects in basal ganglia D,: D3 uptake. The

repeated measures ANOVA did find a marginally significant difference on the teft. but this analysis used only three subjects and the effect was not significant when the the mean slope method was used.

Some caution should be used in interpreting these rest&s. The numbers were small (eight unmedicated GTS patients, seven medicated GTS patients, and six control subjects). Thus, a Type II error cannot be excluded. We considered and excluded the possibility of “contamination” or mislabeling of a patient taking occult Dz blocking agents as being unmedicated. The unmedicated group consisted of four drug-naive subjects and four subjects who had not taken medications for more than 3 months. Subanalyses of these two subgroups revealed similar results.

Differences in regional brain volume could conceivably have influenced our

results. The most recent CT and MRI evidence indicates that GTS subjects have abnormally small lei’t basal ganglia or globus pallidus. This decrease in left-sided caudate volume might explain the transient lag in GTS caudate D, receptor binding (Fig. 2). ‘Thus, decreased caudate volume, with decreased initial first pass of IBZM. might influence or partially explain our present results. We are investigating subjects in this study with MRI to yuantitate volume of the basal ganglia, frontal cortex, and visual cortex.

201

Finally, there are methodological questions about the specific ability of 12%IBZM to identify D,/D, receptors and the precise time at which the SPECT picture changes from one of general blood flow to more specific D, binding. Studies show that 1231-IBZM binding to postsynaptic D, receptors begins reliably at 20 minutes after injection, with peak binding at 35-40 minutes after injection (Kung et al., 1989, 1990; Costa et al., 1990; Brucke et al., 1991; Malison et al., 1991). These results could also be influenced by different levels of endogenous dopamine between control subjects and GTS subjects. For example, it is conceivable that GTS subjects might have higher levels of DJD, receptors, but that the higher number is offset by higher resting levels of endogenous dopamine, thereby occupying and blocking some of the receptors.

The present findings do not appear to support the theory of heightened or excessive D, receptor binding of dopamine in GTS. The preliminary findings need to be replicated in other centers and with other D, iigands, however, before firm conclusions can be drawn. It is to be hoped that functional neuroimaging studies with specific neurolig~ds will ultimately prove to be a powerful tool in unraveling the pathophysiology of Tourette’s Syndrome.

Acknowledgments. We are gratefuf to the individuals who participated in this study, to the U.K. Tourette Syndrome Association for their support, and to Dr. John Bartko for statistical consultations. We would also like to thank Dr. Howard Ring for helpful discussions about SPECT techniques and data analysis. Dr. Trimble thanks the Mental Health Foundation (U.K.). Drs. George and Trimble thank Mrs. Raymond Way and the Raymond Way Fund.

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