Brain (1991), 114, 2191-2202

OBSESSIONAL SLOWNESS FUNCTIONAL STUDIES WITH POSITRON EMISSION TOMOGRAPHY by G. V. SAWLE, 12 N. F. HYMAS, 3 A. J. LEES1 and R. S. J. FRACKOWIAK1'2 (From the lMRC Cyclotron Unit, Clinical Sciences Section, Hammersmith Hospital, London, the ^•Department of Clinical Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, and the ^Department of Psychiatry, Fulboum Hospital, Cambridge, UK)

SUMMARY

INTRODUCTION

Many patients with Obsessive-Compulsive Disorder (OCD) show a limited degree of slowness in the execution of everyday tasks which is secondary to rituals, other compulsive actions or obsessional thoughts. In some patients, however, slowness dominates the clinical picture and the term 'primary obsessional slowness' has been used (Rachman, 1974). Such patients are meticulous and subject to continual mental checking. Others fractionate complex motor activities (such as cleaning their teeth) into component parts which are then carried out serially with a loss of fluency. Clinical examination of patients with OS reveals a number of neurological signs, such as a glabellar tap, cogwheel rigidity, upper-limb asynkinesia, simple and complex adventitious movements and perseveration. These motor findings have been described fully in a group of 18 OS patients reported by Hymas et al. (1991) (following paper). Whilst some of these signs are classically associated with disease of the extrapyramidal motor system, others may be seen in patients with frontal lobe disease. The purpose of this study was to quantitate regional oxygen metabolism within frontal cortex and dopaminergic function within the nigrostriatal system, to identify functional correlates of these neurological signs, and of the patients' slowness. Correspondence to: Dr G. V. Sawle, MRC Cyclotron Unit, Clinical Sciences Section, Hammersmith Hospital, DiiCane Road, London W12 OHS, UK. © Oxford University Press 1991

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Patients with Obsessional Slowness (OS) exhibit extreme slowness in the execution of some everyday tasks, such as washing and eating. This may be due to time-consuming rituals, checking behaviour and compulsions. On examination some have neurological signs such as a glabellar tap reflex, cogwheel rigidity or abnormal postures. The purpose of this study was to establish a functional explanation for slowness in this patient group. We have studied 6 OS patients using positron emission tomography (PET) with l5Oxygen to measure regional cerebral oxygen metabolism and [18F]-6-Fluorodopa (18F-dopa) to assess the integrity of the presynaptic nigrostriatal system. The findings were of focal hypermetabolism in orbital frontal, premotor and midfrontal cortex, whilst dopa uptake into caudate, putamen and medial frontal cortex was normal. The relationship of these findings to the patients' slowness is discussed.

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Four of the patients with OS described by Hymas et al. (1991) (following paper) and two similar cases are the subject of this study. In all patients a formal diagnosis of obsessive-compulsive disorder was made according to DSM-III R criteria (American Psychiatric Association, 1987). Tables 1 and 2 summarize some of the clinical features of the patients scanned. Further details are given in Hymas et al. (1991) (following paper). Case 1 [Case O in Hymas et al. (1991), following paper] A male aged 37 yrs with a 26-yr history of slowness in most daily activities, taking several hours to turn on the television or open a door. He displayed repetitive ritualistic behaviour and frequent checking and complained of being unable to start things because of 'a kind of inertia'. He had been confined to home for 4 yrs and to bedroom/toilet for 12 mths. Drugs at the time of scan: diazepam 20 mg, prothiaden 100 mg and codeine phosphate+paracetamol 6.5 g daily. There was no evidence of neuroleptic treatment. Case 2 [Case L in Hymas et al. (1991), following paper] A male aged 20 yrs with a 4-yr history of slowness with repetition and slowness in the initiation of movement such as walking through a door. He was receiving no drug treatment. Case 3 [Case M in Hymas et al. (1991), following paper] A male aged 56 yrs with a 25-yr history of slowness, housebound for 10 yrs with repetition of actions and fears of contamination or electrocution. Bathing could take up to 12 h. On no drug treatment.

TABLE 1. SUMMARY OF OBSESSIONAL SLOWNESS PATIENTS STUDIED WITH PET Case no. 1 2 3 4 5 6

Duration (yrs) 26 4 25 8 17 15

Age 37 20 36 24 39 30

Depressed No No No Yes No No

Drug treatment at time of PET scanning Diazepam + Dothiepin Nil Nil Lofepramine* Nil** Pimozide + Clomipramine

Oxygen metabolism Yes Yes Yes Yes Yes Yes

•Previously treated with fluphenazine. "Previously treated with chlorpromazine.

TABLE 2. SUMMARY OF MOTOR ABNORMALITIES IN OBSESSIONAL SLOWNESS PATIENTS Case no.

Age

1 2 3 4 5 6

37 20 56 24 39 30

Speech

Posture

Upper limbs

Gait

For complete details of the motor findings on examination, see Hymas et al. (1991) (following paper).

Dopa uptak Yes Yes Yes Yes Yes No

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Case 4 A male aged 24 yrs with a 8-yr history of slowness, with fears of contamination and checking. Using the toilet to urinate took up to 2 h, opening a door by the handle would take 10 min and switching a light or a tap off 15 min. He worried that his hands had become contaminated with urine and would sometimes spend 12 h at night washing them. He was also mildly depressed. He had received 2 doses of depot

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fluphenazine, 12 and 9 mths prior to his PET scans. This treatment induced bradykinesia, tremor and rigidity which resolved on discontinuation of treatment and prior to PET scanning. Drug treatment at time of scanning: lofepramine 210 mg daily. Case 5 A male aged 39 yrs with a 17-yr history of slowness with difficulty initiating movements such as writing. Getting undressed and into bed took 2 h, brushing his teeth took 20 min and it would take 3 min to open a door by the handle; such everyday activities were disrupted by continual checking. He was stopped by the police on several occasions and asked why he was driving so slowly. He had been treated with chlorpromazine 300 mg daily approximately 18 mths prior to his PET scan but had received no medication for at least a year at the time of scanning. Case 6 [Case F in Hymas et al. (1991), following paper] A male aged 30 yrs with a 15-yr history of slowness, being distracted by his surroundings and particularly compelled to touch and pick things up from his path. Bathing took approximately 2 h. At the time of PET scanning, he was taking pimozide 10 mg and clomipramine 10 mg daily. PRACTICAL PROCEDURE

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All patients underwent scanning with l5Oxygen labelled CO2, O2 and CO to measure regional oxygen metabolism, cerebral blood flow, oxygen extraction ratio and blood volume. Five patients also underwent 18 F-dopa scans to measure presynaptic nigrostriatal function. PET scans were performed on the CTI 931/12/8 (CTI, Knoxville, Tennessee, USA) scanner at the MRC Cyclotron Unit at the Hammersmith Hospital. The performance characteristics of this scanner have been described by Spinks et al. (1988). Ethical permission for these studies and for studies on normal volunteers was obtained from the ethical committee of the Royal Postgraduate Medical School, Hammersmith Hospital. Approval to administer radiolabelled gases and ligands was obtained from the Administration of Radioactive Substances Advisory Committee of the United Kingdom (ARSAC). Written consent was obtained from all subjects after a full explanation of the procedure. For each study a 22-gauge arterial cannula was inserted into the radial artery after subcutaneous infiltration with bupivicaine 1%. The subject's head was supported and immobilized in an individually moulded polyurethane support and positioned in the scanner with the orbitomeatal line parallel to the detector rings. Subjects were scanned with eyes and ears open, looking towards the dimly illuminated ceiling in a quiet room. A 10 min transmission scan was collected using a retractable 68Gallium/68Germanium ring source. For oxygen studies, data were collected for two scans each of 10 min duration, during inhalation of C' 5 O 2 and I5 O 2 containing 0.75 megabequerels (MBq) ml" 1 . Ten min washout time followed each scan. A further 6 min scan was collected following a 4 min inhalation of C"O. Subjects were instructed to breathe normally during gas inhalation. Parametric images of regional cerebral blood flow, regional cerebral oxygen metabolism, oxygen extraction ratio and regional cerebral blood volume were calculated from the emission scans using arterial oxygen content and whole blood and plasma counts measured in triplicate during each scan (Frackowiak et al., 1980; Lammertsma and Jones, 1983). For 18F-dopa studies, subjects received 100 mg of carbidopa 1 h before the study and a further 50 mg immediately before scanning. Each subject received approximately 140 MBq of l8F-dopa by intravenous infusion over 2 min. Dynamic emission scans were collected for the following 124 min divided into 28 time frames. Both the 13O2 and the l8F-dopa scans were reconstructed into 15 planes with a resolution of 8.5x8.5x7.0 mm without interplane deadspace. Scans were analysed using image analysis software (Analyze version 2.0, BRU, Mayo Foundation, USA) on SUN 3/60 Workstations. For "Oxygen studies, a series of approximately 600 cortical and subcortical regions of interest was defined and named from the coplanar stereotaxic brain atlas of Talairach and Toumoux (1988). These regions were chosen empirically in order to sample the major anatomical subdivisions of the frontal, temporal, parietal and occipital cortex, cerebellum, striatum and thalamus. For the larger anatomical areas, such as visual association cortex, multiple regions were used. For smaller structures, such as the head of the caudate nucleus, a single region was placed on each of a series of contiguous atlas planes. For each scan the 15 plane image set was interpolated to 43 planes and the degree and angle of displacement from the intercommissural (ACPC) line was measured (Friston et al., 1989). A series of

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TABLE 3. REGIONAL/GLOBAL CEREBRAL METABOLIC RATE FOR OXYGEN

Cortical region (Brodmann no.) Visual (17) Auditory (41 and 42) Sensorimotor (1 —4) Visual association ( 1 8 - 2 1 , 37) Auditory association (22) Superior parietal (5, 7) Inferior parietal (39, 40) Temporal pole (38) Hippocampus (34) Prcmotor (6, 8, 44) Superior frontal (9) Midfrontal (46) Inferior frontal (45) Frontal pole (10) Orbital (11, 47) Medial frontal (32) Anterior cingulatc (24) Caudate Putamen Thalamus Cerebellum Corona radiata

Normal volunteer (n = 6) Left Right Mean ± SD Mean ± SD

1.18±0.07 1.12±0.19 0.92±0.08 1.01 ±0.02 1.08*0.06 1.01 ±0.07 0.98±0.02 0.85±0.10 0.90*0.14 0.91 ±0.04 0.93 ±0.06 0.90±0.04 0.92 ±0.05 0.91 ±0.05 0.91 ±0.04 0.99*0.04 0.96±0.10 0.93 ±0.09 l.ll±0.14 1.06*0.06 0.99*0.13 0.51 ±0.21

1.09±0.18 1.I3±O.17 0.89*0.03 0.99*0.02 1.04±0.12 0.99*0.09 0.97*0.05 0.85*0.07 0.74 ±0.15 0.87 ±0.04 0.92*0.07 0.90±0.04 0.95*0.07 0.88 ±0.03 0.92*0.03 0.94*0.04 0.85*0.10 0.95*0.09 1.00±0.11 0.94±0.15 0.99 ±0.08 0.48 ±0.19

Obsessional slowness (n

Left Mean±SD

.08±0.14 .07*0.09 ().96±0.06 .00*0.03 .03±0.13 .00*0.08 .04*0.05 0.93*0.08 0.85 ±0.05 0.96*0.03* 0.96*0.06 0.98*0.06* .00*0.11 0.96±0.05 .01*0.07* 0.96*0.11 0.91*0.07 0.94*0.28 .17*0.09 .05±0.12 .10*0.04 0.38 ±0.03

= 6) Right Mean±SD

1.09*0.07 1.04*0.17 0.96*0.06* 0.98*0.06 1.06*0.10 0.98*0.07 0.96*0.02 0.89*0.10 0.80*0.07 0.95*0.06* 0.94*0.07 0.97*0.05* 0.93*0.15 0.97*0.07* 1.03*0.06** 0.91*0.15 0.80*0.11 1.03*0.08 1.10*0.06 0.95*0.08 1.09*0.08 0.41*0.06

•Indicates regions for which P < 0.05 (Mest and Mann-Whitney U test). "Indicates regions for which P < 0.02 (f-test and Mann-Whitney U test).

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coordinates was then calculated using Microsoft Excel 2.2 (Microsoft Corp., USA) on an Apple Macintosh SE/30 computer (Apple Computer Inc., USA), transferring the 600 atlas coordinates into image space. These regions were transferred to the SUN 3/60 and made available within the Analyze program. Because of the difference in orientation between the images and atlas brains, some of the atlas coordinates fell (when reorientated) midway between adjacent image planes. These coordinates were discarded (approximately 200 in each case), and only coordinates which fell close to the original 15 plane data were accepted as stereotactically positioned. Each of the original 15 image planes was viewed in turn and the position of each region was verified and adjusted in turn to compensate for minor non-linear variations in anatomy, such as those resulting from variations in ventricular size. Each region was of size 4 x 4 pixels (8.2x8.2 mm) or 5 x 3 pixels (10.2x6.2 mm) (1 pixel = 2.05 mm). A total of approximately 400 regions were therefore stereotactically placed for each subject, sampling regional activity within the prefrontal region in the greatest detail. Data were generated for each named region and returned to the Macintosh SE/30 for further analysis. The data were averaged according to the anatomical regions listed in Table 3. These regional values were normalized for intersubject variation in global metabolic rate. For 18F-dopa studies the position of striatal structures was determined by inspection, with reference to the stereotactic atlas of Talairach and Toumoux (1988). Regions of interest were defined for caudate (1 region each side of 4 x 4 pixels), putamen (3 regions each side of 4 x 4 pixels, placed contiguously along the axis of the putamen), medial frontal cortex (1 circular region of diameter 8 pixels), occipital lobe (1 circular region each side of diameter 16 pixels) and cerebellum (dimensions as for occipital regions). All regions of interest were defined on two adjacent planes and average values for each anatomical structure were calculated. Regional time activity curves were plotted and the data were analysed using a multiple time graphical analysis approach (Patlak and Blasberg, 1985; Martin et al., 1989). Cerebellar activity was subtracted from striatal activity and the arterial plasma activity curve corrected for the accumulation of 3-O-Methyl dopa, assuming a linear increase in the ratio of 3-O-Methyl dopa:Fluorodopa with time (W. R. Martin, personal communication). An influx constant (Kj) was calculated from the linear regression

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of regional-cerebellar activity/corrected plasma activity vs integrated corrected plasma activity/corrected plasma activity for data collected between 30 and 120 min after tracer injection (Sawle et al., 1990). A series of 6 healthy male volunteers (age 36 ± 11 yrs) underwent identical studies of regional "Oxygen metabolism and l8F-dopa uptake.- These volunteers were all free of neurological signs. Although they did not undergo extensive neuropsychiatric examination, none described any symptoms of OCD and none had any clinical evidence of slowness. All scored 30/30 on the Mini Mental test (Folstein et al., 1975). RESULTS

DISCUSSION

The search for functional and pathological correlates of obsessive-compulsive behaviour has been to some extent promoted by observed correlations with other conditions, including diabetes insipidus (Barton, 1976), epilepsy (Kettl and Marks, 1986), birth injury (Capstick and Seldrup, 1977), head injury (McKeon et al., 1984) and encephalitis lethargica (Schilder, 1938). Furthermore, patients with Sydenham's chorea have a higher prevalence of obsessional thoughts and compulsive behaviour than patients with rheumatic fever (Swedo et al., 1989a), and patients with frontal gliomas may have transient feelings of compulsion (Ward, 1988). Surgical attention in OCD has focused on the frontal lobe,

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Regional cerebral metabolic oxygen metabolism data for patients and controls have been normalized to global metabolic rate and are given in Table 3. Cortical regions are presented according to functional areas, such as primary sensory cortex and association cortex. The prefrontal area has been analysed in the greatest detail, in order to dissect any regional metabolic differences between orbital cortex and other prefrontal regions. Left and right cortical values have been analysed separately. Data are presented for all regions studied including, for example, visual association cortex and thalamus, where we did not expect to find any abnormality. We have tested for difference in the two group means using an unpaired two-tailed t test. Because of small patient numbers and the multiplicity of regions studied we have not applied Bonferroni's correction, as this would render our analysis powerless to detect any small but potentially important group differences. We therefore recognize the potential for a type I error. Because our data might not be normally distributed, we also analysed it using the non-parametric Mann-Whitney U test, which gave similar levels of statistical significance. In Table 3, those regions where P < 0.05 or < 0.02 are indicated * and **, respectively. If the P values of < 0.05 were all due to type I errors, however, we would not expect similar cortical regions to be affected in the two hemispheres. The three regions which are bilaterally hypermetabolic in the obsessional slowness patients are orbital frontal cortex (Brodmann 11 and 47), premotor cortex (Brodmann 6, 8 and 44) and midfrontal cortex (Brodmann 46). The individual patient data for these three anatomical areas are shown in Fig. 1. Although there are significant group differences for these regions, there was no single anatomical region for which all of the patient values were greater than all of the control values. Kj values for 18F-dopa uptake into caudate and putamen for patients and control subjects are given in Table 4. There are no significant differences in striatal l8F-dopa uptake between the patients and control subjects. Kj values for medial frontal cortex and occipital cortex were likewise similar in the two groups (data not shown).

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G. V. SAWLE AND OTHERS Orbital frontal (11,47)

Premotor (6,8,44)

Midfrontal (46)

i.i-i

a 5a

e

1.0-

•

3

0.9-

5 B

a 0.8

J

OS

N

OS

OS

FIG. 1. Scattergraph to show the individual metabolic ratios (region/global) for oxygen metabolism in the three cortical areas found to be significantly hypermetabolic in the obsessional slowness group. Left (open squares) and right (filled squares) are shown for each patient. N = normal subjects, OS = obsessional slowness patients.

Region Left caudate Right caudate Left putamen Right putamen Medial frontal cortex

Obsessional slowness (n =5) Mean ± SD 0.0164±0.0026 0.0159 ±0.0037 0.0174 ±0.0039 0.0165±0.0O49 0.0034±0.0011

Normal volunteer (n = 6) Mean ± SD 0.0163±0.0027 0.0159 ±0.0033 0.0152 ±0.0025 O.O153±O.OO3O 0.0029±0.0011

K; values calculated by graphical analysis using plasma as input function.

and indeed partial isolation of either orbital frontal cortex (Bridges et al., 1973) or cingulate cortex (Tippin and Henn, 1982) from surrounding structures has often resulted in clinical improvement. Previous PET studies In the context of the above findings, OCD has been studied with PET using l8 F-fluorodeoxyglucose to quantify regional glucose metabolic rate (Baxter et al., 1987, 1988; Nordahl et al., 1989; Swedo et al., 19896). The principal findings have been within frontal lobe and caudate. Baxter et al. (1987) reported an increase in glucose metabolic rate in OCD within the left orbital gyrus and both caudate nuclei, although the caudate values fell to normal when normalized to the ipsilateral hemisphere. Subsequently, Baxter et al. (1988) reported significantly higher glucose metabolic rate in non^depressed OCD patients for whole hemisphere values, right and left orbital cortex

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TABLE 4. REGIONAL "F-DOPA K^

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and caudate nuclei. The orbital cortex (but not the caudate) values remained elevated after normalization to hemisphere values. Nordahl et al. (1989) studied OCD patients and controls during a continuous auditory discrimination task designed to evaluate the functional localization of sustained attention. A bilateral increase in normalized orbital frontal glucose metabolism was noted in the patient group. No changes were recorded in the basal ganglia. Small and unexplained reductions in glucose metabolism were noted in right parietal and left parieto-occipital regions. Swedo et al. (1989ft) measured regional glucose metabolism in childhood-onset OCD. Regional metabolic rates were significantly elevated above control values for bilateral prefrontal, left orbital, left premotor, right sensorimotor, left inferior temporal, left paracentral, right cerebellar, right thalamus, left and right anterior cingulate. When normalized to whole hemisphere values, however, only the right prefrontal and left anterior cingulate values remained abnormal. Caudate values were normal in all analyses. Our findings differ from the above studies in several respects. We report a significant bilateral elevation of orbital cortex (Brodmann 11 and 47), premotor cortex (Brodmann 6, 8 and 44) and midfrontal (Brodmann 46) metabolic rate after normalization to mean ipsilateral cortex values. Hypermetabolism in orbital cortex has been suggested by all four previous studies, and is most likely a finding common to many patients with OCD. In contrast, we believe this is the first report of an abnormality in premotor cortex and midfrontal cortex in this condition. Possible explanations for this include differences in scanner resolution, scanning technique, methods of analysis or a difference in patients studied. Baxter et al. (1987, 1988) have used a camera with lower resolution ( l l x l l x 12.5 mm) than this study whilst Swedo et al. (1989ft) have reconstructed their images to a higher transaxial resolution (6x6 mm) yet have a lower axial resolution (10 mm). Reconstructing into a higher resolution reduces the signal-to-noise ratio, and this might have contributed to the Swedo etal.{\989ft) finding of scattered areas of hypermetabolism throughout both hemispheres. The four previous studies all measured glucose metabolism, whereas we measured oxygen metabolism. Glucose and oxygen metabolism are normally closely coupled, and it is unlikely that this difference in technique is significant. Accurate anatomical localization within PET data depends upon both axial and transaxial resolution. Baxter et al. (1987, 1988) and Swedo et al. (1989ft) assumed that the brain has a constant alignment to the inferior orbitomeatal line and positioned their regions-of-interest by eye using an atlas of brain sections taken in that plane. In view of our greater axial (and transaxial) resolution, we were able to accurately image the intercommissural line and hence align our image data with a set of transformed atlas coordinates. Inter-subject averaging of data from studies where anatomical regions have been stereotactically positioned may improve signal-to-noise ratio further. Nordahl etal. (1989) studied their patients during an auditory discrimination task. This seems not to have affected the findings of orbital frontal hypermetabolism (a finding common to all of these studies). The only finding peculiar to their study was the report of parietal and parieto-occipital hypometabolism, which may be either related to the activation paradigm used, or perhaps to the exploratory statistical approach adopted in most of these studies. Clearly the statistical power of the observation of hypermetabolism in midfrontal and premotor cortex is low and this finding should be confirmed through replication

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before we can be certain of its validity. If genuine, however, we suggest that these areas of hypermetabolism might reasonably be included within the neural substrate of our patients' slowness.

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The motor effects of frontal cortex lesions The effect of lesions within premotor cortex in man have been described in patients with cerebral tumours or following cerebral infarction. Freund and Hummelsheim (1985) described a disorder of movement with proximal arm weakness and a limb-kinetic apraxia. They noted that 'the movement disorder became apparent when a certain temporal sequence of activities of proximal muscles of both sides was necessary for a movement'. Passingham (1987) discusses the subdivision of premotor areas in the direction of movement. He suggests that the lateral premotor cortex (lateral Brodmann 6) directs movement on the basis of visual and auditory cues from the outside environment, and that the supplementary motor area (medial Brodmann 6) directs actions on the basis of proprioceptive cues concerning the animals's own actions. Patients with obsessional slowness are unable to move at normal speed when left alone, yet under direction from others may improve their speed to near-normal levels. Eslinger and Damasio (1985) reported a patient following an extensive frontal resection to remove a meningioma. The patient became indecisive and extremely slow: 'He took about 2 h to get ready for work in the morning and some days were consumed entirely by shaving and hair washing.' CT and MRI studies showed bilateral damage to orbital and medial frontal cortex and subcortical white matter, and damage to the dorsolateral cortex on the right side only. Not surprisingly, a 133Xenon single photon emission tomography (SPET) study showed low flow corresponding to the area of ablation. Goldman-Rakic (1987) has reviewed evidence regarding motor functions of cortex around the principal sulcus (Brodmann 46 in man, Walker 46 in monkey). This area has prominent connections with basal ganglia and deep layers of the superior colliculus, with reciprocal connections to supplementary motor area (SMA) and the premotor cortex. It is suggested that the principal sulcus can influence delayed-responding, though only when inner models of reality are used to govern responses is the prefrontal cortex pre-eminently engaged. This is of relevance to our obsessional slowness patients, as they are constantly planning movements which may be extremely delayed in execution. With external prompting, however, this delay may often be circumvented with an increase in the speed of movement. We have studied our patients at rest, and yet they have hypermetabolism within premotor cortex. We also recorded an increase in metabolic rate within primary sensorimotor cortex (Brodmann 1 to 4) on the right side only. In healthy volunteers these areas can be activated during repetitive movement, with an increase in regional cerebral blood flow in both primary motor cortex and SMA (Fox et al., 1983; Roland, 1987). This area is hypermetabolic in patients with obsessional slowness even at rest, and it would be of interest to measure regional changes during self-paced and externally paced movement in these patients. A slowly increasing negative potential, recorded over the fronto-central scalp 1 — 2 s prior to self-paced movements in healthy subjects has been termed the readiness potential or bereitschaftspotential (Deecke et al., 1969). It has been suggested that there are at least two principal generators of this potential, the supplementary motor area and the

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primary motor cortex, the former probably bilateral and the latter contralateral to subsequent movement (Deecke, 1987). The hypermetabolism in premotor cortex (including the supplementary motor area) in obsessional slowness patients may thus be related to an elaboration of the neural substrate of this potential. To our knowledge, such electrophysiological recordings have not been performed in these patients. Given that these patients report a lengthened preparation for movement and furthermore have increased oxygen metabolism within some frontal regions, we still have no explanation for why normal movement does not proceed. Synaptic firing within midfrontal cortex, orbital cortex and premotor cortex might be inhibitory rather than excitatory, perhaps relating to the blockade of movement rather dian its preparation.

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Dopa studies Baxter et al. (1987) reported an increase in caudate glucose metabolism in acute OCD patients, whilst Swedo et al. (19896) found normal values in young adults with childhood-onset OCD. It was suggested that the caudate might be hypermetabolic in early disease, with metabolic rate falling to normal when the disease becomes entrenched. Luxenberg et al. (1988) measured caudate and lenticular volume in OCD, reporting a lower caudate volume in patients than in controls. Weilburg et al. (1989) described a patient with obsessive-compulsive disorder in whom magnetic resonance imaging revealed a decrease in volume of the left caudate and a band of prolonged T, and T2 signal in the left putamen, although the patient had a history of birth trauma requiring neonatal intensive care, and these findings may have been incidental to his OCD. Laplane et al. (1984, 1989) reported 8 patients with lentiform lesions, mostly within the pallidum. All were thought to be the consequence of anoxic or metabolic encephalopathy. These patients exhibited inertia with loss of drive and in some cases compulsive and obsessional behaviour. Seven of the patients had 18F-fluorodeoxyglucose PET studies which revealed a relative hypometabolism of striatum and prefrontal cortex. Whilst these findings contrast with the hyper metabolism in patients with classical OCD, the anatomical congruency is striking. Two of us (N.F.H. and A.J.L.) have observed a shortlived response to L-dopa in some patients with obsessional slowness. In view of this observation, the rich connections of caudate and putamen with frontal cortex (Yeterian and Van Hoesen, 1978) and the motor consequences of striatal disease, we were anxious to examine both metabolic rate and 18F-dopa uptake in striatal tissue. Striatal l8F-dopa accumulation represents uptake into nerve terminals, conversion into l8F-dopamine by dopa decarboxylase, and subsequent concentration and storage in terminal neurotransmitter vesicles (Firnau etal., 1987). Although several approaches to the quantitative analysis of l8F-dopa uptake have been developed (Martin et al., 1989; Sawle et al., 1990; Tedroff et al., 1990), none is able to measure endogenous dopamine synthesis as the conversion of tyrosine to L-dopa is the rate limiting step in the dopamine synthetic pathway. Nevertheless, a reduction in l8F-dopa uptake is believed to reflect a reduction in the number of functioning nigrostriatal dopaminergic neurons. Patients with early Parkinson's disease may have a minimal evidence of akinesia and yet at the time of presentation have lost 50 — 80% of nigrostriatal neurons (Jellinger, 1987). l8F-dopa scans show a major reduction of striatal uptake in such patients (Leenders, 1986). The normal l8F-dopa uptake in primary obsessional slowness

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patients suggests that their extreme slowness is not related to a loss or dysfunction of nigrostriatal dopaminergic neurons. Although several patients were taking benzodiazepine or antidepressant medication at the time of their l8F-dopa scans, none had received major tranquillizers for a considerable period of time. The effect of medication upon the scan results is not known although we are unaware of any evidence suggesting that this medication would give a spuriously high l8F-dopa uptake, masking a true reduction of nerve terminal function.

ACKNOWLEDGEMENTS G.V.S. is supported by the Parkinson's Disease Society of Great Britain. We thank colleagues in the Physics and Radiochemistry sections of the Cyclotron Unit for their expertise which made these studies possible. We also thank Ms C. J. V. Taylor and Mr G. C. Lewington for their help with scanning.

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glucose metabolic rates in obsessive-compulsive disorder: a comparison with rates in unipolar depression and in normal controls. Archives of General Psychiatry, 44, 211—218. BAXTER LR, SCHWARTZ JM, MAZZIOTTA JC, PHELPS ME, PAHL JJ, GUZE BH et al. (1988) Cerebral

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Relationship between obsessional slowness and Parkinson's disease Most of the neurological signs recorded in our patients, such as positive glabellar tap or stooped posture, are common findings in Parkinson's disease. Whilst we have no evidence for a nigrostriatal dopaminergic defect in these patients, the structures in which we have demonstrated oxygen hypermetabolism are involved in both the 'complex' loop (pre-frontal cortex — caudate — globus pallidus and substantia nigra — ventral anterior thalamus — prefrontal cortex) and the 'motor' loop (premotor and sensory-motor cortex — putamen — globus pallidus and substantia nigra — ventrolateral thalamus — premotor and sensorimotor cortex), two of the principal neuronal circuits involving the basal ganglia (DeLong et al., 1983). The mechanism of the short-lived clinical improvement seen in some patients after treatment with L-dopa is unclear but presumably is related to function within these circuits. In summary, our obsessional slowness patients have bilaterally increased oxygen metabolism at rest in orbital frontal cortex, premotor cortex and midfrontal cortex. Orbital frontal hypermetabolism has been reported in four previous studies of OCD, whereas hypermetabolism within premotor and midfrontal cortex is a novel finding. We suggest that this increased activity is related to these patients' internal preparation for movement.

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