Glucose metabolism in the brain of patients with essential tremor

lournal oJ the Neurological Science,s, 114 (1993) 45-48 '£, 1993 Elsevier Science Publishers B V All rights reserved 0022-510X/93/$06 00

45

JNS 03892

Glucose metabolism in the brain of patients with essential tremor Mark Hallett and Richard M. Dubinsky Human Motor Control Section, Medwal Neurology Branch, National blstmae of Neurological Dt~order~ and Stroke, National bzstttutes ot Health, Bethesda, All), USA

(Recewed 7 May, 1992) (Accepted 111July, 1092)

Key words' Essential tremor, Positron emission tomography, Glucose metabolism, Cercbellum, Inferior ohvary nucleus; Thalamus Summary U s i n g p o s i t r o n emission t o m o g r a p h y with [l~F]fluoro-2-deoxyglucose, we d e t e r m i n e d the regional cerebral metabolic rate of glucose utilization at rest in 8 m e d i c a t i o n - f r e e patients with essential t r e m o r and m 10 n o r m a l subjects Taking the m e t a b o h c values of regions of interest as ratios to the m e a n h e m i s p h e r i c metabolism, the p a t i e n t s showed significant glucose hypermetabolism of the medulla and t h a l a m i but not of the c e r e b e l l a r cortex This study lends suppol t to e a r h e r suggestions that circuits mvolvlng the inferior ohvary nuclei in the medulla and the thalmus are involved in the g e n e r a t i o n of essent|al tremor_

Introduction Essential tremor is a common movement disorder, yet there is no estabhshed pathological lesion associated with ~t (Lee 1987) There ~s even debate about the principal site ot the abnormahty and whether it ~s in the central nervous system or the peripheral nervous system There is, however, evidence that tremor is associated with areas of increased actwlty in the central nervous system. Recordings at the time of stereotaxic surgery in patients with essential tremor have revealed bursting neurons in the thalamus (NarabayashJ 1989). Animal studies attempting to model essential tremor with the tremorgenlc agents harmlne and harmaline have demonstrated rhythmical firing of cells in the Inferior ollvary nucleus, cerebellum, and thalamus (Longo and Massottl 1985). Positron emlssion tomography with [~F]fluoro-2-deoxyglucose ( F D G - P E T ) has been used extenswely to investigate the regional metabolism of the brain. The

1 Pre~ent addres~ Department of Neurology, Umverslty of Kansas Medical Center. Kansas C~ty, KS 66160-7314, USA Correspondence to Mark Hallett, M D , Budding 10, Room 5N226, NINDS, NIH, Bethesda, MD 20892, USA

regional cerebral metabolic rate of glucose utihzatlon (rCMRGIc) Is beheved to indicate regional cerebral synaptic activity (Kadekaro et al_ 1985, 1987). We used F D G - P E T to investigate a series of patients w~th essential tremor in order to shed some light on the pathophyslology of the disorder.

Patients and methods We studied 8 patients with essential tremor (5 men, 3 women), aged 25-72 years (mean, 50 years), and 10 normal subjects (8 men, 2 women), aged 24-66 years (mean, 44 years) All of the patients had action-induced tremor without rest tremor, and no evidence of other nervous system disease The patients and control subjects were medication free for 2 weeks before the PET scans. The protocol was approved by the lnstitute's clinical investigattonal review committee, and all subjects gave their written informed consent for the study Imaging was done with the NINDS-budt Neuro-PET, which scans 7 simultaneous slices The in-plane resolution is 6 - 7 mm (full width at half maximum) and the slice thickness is 11-12 ram. Corrections for scattered and random coincidences and for attenuation are incorporated. The attenuation correction is calculated from the scalp outline, which is placed automatically by

46 thc computer and then adJusted, if needed, by the operator; it includes a bone correction, based on a nominal skull thickness Because of the complex bone structure in the posterior fossa, the use of a calculated attenuation correction reqmres some comment To begin w~th, the patient population values were compared with corresponding values in a control group and inferences were drawn from the differences, an approach that basically ehmmates systematic errors common to both groups, such as those assoctated with attenuatton. Further, when 19 normal subjects studied on the Neuro-PET were compared with 17 normal subjects studted on the Scanditrontx PC2048-15B, which uses a measured attenuation correction, the metabohc rates agreed to w~thln 2% m the cerebellum and to within 8% in the brain stem (M.J Fulham, unpublished data) This agreement was comparable to that obtained between two different Scand~tronLx scanners, both of which used a measured attenuation correction_ Therefore, we are confident that the method of attenuation correction we used d~d not lead to any significant error in our conclusions The F D G - P E T procedure has been reported previously (D1 Chirp et al. 1984; Hatazawa et al. 1987). The subjects were at rest, and their eyes were patched and ears plugged. A 5-mCl dose of F D G was given intravenously and followed by either arterml or arterializedvenous sampling to measure the plasma concentration of FDG. Beginning about 30 min after the injection, 6 sequentml PET scans were taken, each taking 7 rain Three scans were taken above and parallel to the canthomeatal hne, with a 4-mm increment between scans, and 3 scans were taken similarly below the canthomeatal hne. The result was 42 interleaved images of the entire brain wtth center-to-center spacing of 4 mm. Regional glucose metabolic rates were obtained by placing 5 regions of interest (ROIs) over the image that best visualized the desired structure, using an atlas of brain structures (DeArmond et al. 1976) as a guide: the medulla (circle, 24 mm in diameter), the thalamus bilaterally (12 × 12 mm squares), and the cerebellar cortex bilaterally (14 mm wide bands) In order to reduce the variabihty from differences in global metabohsm, each value of rCMRGIc was normalized to the mean "hemispheric" metabolism (both hemispheres) of the same subject, measured at the level with the best representation of the basal ganglia.

Statistical analysts Statistical analysis of the data was performed by repeated-measures analysis of variance (ANOVA), usmg the 5 normalized R O I s as the repeated measures. Post hoc analysis was performed using Scheffe's F-test. The level of significance was set at P < 0.05.

Results The A N O V A showed a significant difference In the rCMRGlc between the groups ( P = 003) Post hoc c o m p a r i s o n s h o w e d significant differences m metabolism between the groups specifically for the medulla and the thalami, but not the cerebellar cortex Mean values for each region are shown in Table 1. In comparislon with the control subjects, the patients had a metabolic increase of 71% in the medulla. The increases in the thalami were 10% and 12%. A similar magnitude of increase was found in the right cerebellar cortex, but because of variabdlty in the metabolism, it did not reach statistical significance_ The PET scans shown in Fig. 1 are typical of the findings m the patients and control subjects The patients' scans showed increases in the rCMRGlc in the brain stem regions encompassing the medulla and the thalami, and often showed a bl-lobed region of mcreased metabolism in the medulla

Discussion The patients with essential tremor at rest showed a marked increase in the rCMRGIc, with the most dramatic increase occurring m the brain stem. We suspect that the inferior olivary nuclei are responsible for the changes, but given the resolution of our technique, It is possible that another structure, or structures, in the medulla ts involved, although it is not apparent what that structure might be if it ~s not the inferior olivary nuclei. The region of increased metabohsm in the medulla often had a bi-lobed appearance, and we have

TABLE 1 R E G I O N A L C E R E B R A L METABOLIC RATE OF G L U C O S E U T I L I Z A T I O N (rCMRGIc) IN PATIENTS W I T H ESSENTIAL T R E M O R A N D N O R M A L SUBJECTS The rCMRGIc values for the regions of interest were normahzed to the mean hemlsphenc value of the rCMRGIc and are expressed as mean + SD. The mean hemispheric values of rCMRGIc are in nag glucose/100 g / r a i n Region of interest

Essential tremor

Normal

Percent change m rCMRGIc

Medulla Cerebellar cortex, right Cerebellar cortex, left Thalamus, right Thalamus, left Mean hemisphere

0 3945:0 135 *

0.231±0 112

+71%

1_0695:0_203

0.9405:0 133

+ 14%

0 958 5:0 369 1 391 5:0,156 * 1 3545:0.124 * 6 568 5:1 692

0.933 + 0 123 1 243 5:0.083 1.234:t:0 74 6.178 5:1 045

+ 3% + 12% + 10% + 6%

* P < 0_05 for comparison wtth normal subjects

47

Fig 1 F D G - P E T scans from a 37-year-old woman with essential tremor and from an age-matched normal subject The scans on the top are from the level of the thalamus, and those on the bottom are from the level i)t the medulla Scahng is the same for each set of scans at the same level The color bar indicates the magmtudes of metabohsm, with red representing the greatest metabohsm The thalamus of the patient (top, right) shows greater metabolism than that of the normal subject The medulla is located just above the middle of the larger bl-lobed cerebellum (arrows)_ The medulla of the patmnt (bottom, right) has a distract bl-lobed appearance and also shows greater metabohsm than that of the normal subject

suggested that thts conflguratton m~ght be due to the inferior olivary nuclei (Dublnsky et al. 1991). The changes in synaptic actlvtty are responsible for the changes in the rCMRGIuc (Kadekaro et al 1985, 1987) If the inferior olivary nuclei are the major sites of mcreased metabolism m essential tremor, there is increased activity of either the spino-ohvary tract or the central tegmental tract, or increased synapttc activity of the ohvary interneurons. The spinocerebellar tract mtght be expected to carry increased afferent acttvity in the presence of tremor. The central tegmental tract m~ght be expected to be more acttve with the voluntary movement needed to manifest the tremor, Because the abnormal hypermetabohsm does not depend on the presence of tremor, however, neither of these mechanisms is obwously operative. Increased intrinsic activity would be expected in the inferior ohvary nuclei If they are the generators of the involuntary movement, and this is the explanation we tentatively favor The inferior ohve has been postulated to be the generator of tremor in the ammal model of essential tremor reduced by the alkaloids harmine and harma-

line. In this model, unit recording in the cat shows rhythmical firing at approximately 10 Hz along the olivocerebellar-bulbospmal pathway, and harmlne has a direct effect on the Inferior olive, with projected effects on the cerebellum, red nucleus, and thalamus (Longo and Massotti 1985) Isolated cells of the inferior ohvary nuclei have a spontaneous hrlng rate close to 2 Hz, which may be synchromzed to a rhythmical 10-Hz discharge of the entire nucleus (Llinfis and Yarom 1988; Llln~s 1989). Harmme further enhances the rhythmicity of this discharge, which is synchronous with the tremor (Lllnfis 1984) The tremor is abolished by ablation of the olive (Lamarre 1975), demonstrating its dependence on ohvary activity The inferior olive continues to fire rhythmically when ~olated from the cerebellum and spinal cord (Longo and Massott~ 1985) Our finding of mcreased glucose metabohsm in the thalamus of the patients is consistent with the considerable evtdence of increased neuronal activtty in the thalamus of patients with essenttal tremor, although the thalamic increases were not as dramatic as those in the inferior ohve_ Neurons in the ventral intermediate nucleus (VIM) of the thalamus show bursting behavior that is synchronous w~th the tremor (Ohye e t a [ . 1982; Narabayashl 1989), and thalamotomy or chrome sttmulatlon of this region abolishes the tremor (Hiral et al 1983, Narabayashl 1989; Benabid et al 1991) Bursting of the neurons ~s present only when there ts tremor (H_ NarabayshI and C. Ohye, personal communications), so this type of behavior cannot explain the increased metabolism found in the resting state It is not clear, however, whether there is any increase m background neuronal actJvity in patients with essential tremor, and this is the observatton needed to correlate w~th our findings. The increases in glucose metabolism found in the inferior ohve and thalamus are compatible given the known anatomical connections and according to the schema proposed by Lllnfis (1984). Therefore, the changes found in the present study fit a single coherent theory Colebatch et al (1990), studying cerebral blood flow with PET and 150-labeled water, observed increased blood flow in the cerebellum of patients with essentJal tremor when the tremor was activated A comparable mcrease occurred when normal subjects mimicked tremor, but not when they maintained a posture. With pseudotremor, several cortical regions were activated that were not activated in the pattents Our results, however, are not dtrectly comparable with theirs, because we studied patients at rest rather than w~th actlvatton and used a different PET modahty Studies in our laboratory (Dubmsky et al 1991) have shown increased glucose metabohsm in the medulla of pattents with palatal myoclonus On PET scans, the region of the medulla involved appears to be similar to

48 the one

involved m essenttal tremor, but

in p a l a t a l

m y o c l o n u s t h e r e a r e n o m e t a b o h c c h a n g e s tn t h e t h a l a mus. Pathological c h a n g e s are often f o u n d m the inferior olivary nuclet of p a t t e n t s wtth palatal m y o c l o n u s , w h t c h l e n d s s u p p o r t to the h y p o t h e s t s that t h e s e nuclet are mvolved m the pathophystology of the dtsorder. T h e f m d m g s m palatal m y o c l o n u s also t e n d to s u b s t a n tiate the concept advanced m the present study that t h e h y p e r m e t a b o h s m f o u n d tn t h e l o w e r b r a m s t e m o f p a t t e n t s w t t h e s s e n t t a l t r e m o r ~s c e n t e r e d in t h e i n f e rior olivary nuclei Acknowledgements We are grateful to Drs Glovanm DI Chiro, Rodney A Brooks, Michael J Fulham, H_ Narabayashl, and C Ohye for helpful discussions, to Ruth Hassanein, Ph D , for stattshcal advice, and to Ms B J HessJe for skillful editing

References Benabid, A L, P Pollak, C Gervason et al (1991) Long-term suppression of tremor by chrontc shmulahon of the ventral ratermediate thalamlc nucleus, Lancet, 337 403-406 Colebatch, J.G, L J Fmdley, R S J. Frackowlak, C D Marsden and D J Brooks (1990) Preliminary report_ activation of the cerebellum m essential tremor, Lancet, 336 1028-1030 DeArmond, S J , M M Fugeo and M M Dewey (1976) Structure of the Human Brain A Photographic Atlas, 2nd edn, Oxford Umversity Press, New York, NY_ Dl Chirp, G , R_A Brooks, N J_ Patronas et al (1984) Issues m the m vwo measurement of glucose metabohsm of human central nervous system tumors, Ann Neurol, 15 (Suppl): S138-S146 Dubmsky, RM., M Hallett, G DI Chirp, M Fulham and J Schwankhaus (1991) Increased glucose metabohsm in the medulla of patients with palatal myoclonus, Neurology, 41 557-562

Hatazawa, J., R A Brooks. G Dl Chirp and S L Bacharach 11987) Glucose Utdlzation rate versus brain size in humans, Neurology, 37 583-588 HJral. T , M_ Mlyazakl, H Nakajlma, T_ Shlbazakl and C Ohyc (1983) The correlahon between tremor characteristics and the predicted volume of effechve lesions m stereotaxic nucleus ventrahs intermedms thalamotomy, Brain, 106' 1001-1018 Kadekaro, M , A M Crane and L Sokoloff (1985) Differential elfects of electrical stimulation of sciatic nerve on metabolic actwity m spinal cord and dorsal root ganglion m the rat, Proc Natl Acad. Scl USA, 82 6010-6013 Kadekaro, M_, W H Vance, M L Terrell et al (1987) Effects of antidromic stimulation of the ventral root on glucose utilization m the ventral horn of the spinal cord m the rat, Proc Natl Acad ScL USA, 84 5492-5495 Lamarre, Y (1975) Tremorgemc mechamsms in primates I n B S Meldrum and C D Marsden (Eds), Primate Models of Neurologic Disorders, Raven Press, New York, NY, pp 23-34 Lee, R G. (1987) The pathophyslology of essential tremor I n C.D Marsden and S Fahn (Eds). Movement Disorders 2, Butterworth, London, pp 423-437 Lhnfis, R R (1984) Rebound excitation as the physiological basis for tremor_ a biophysical study of the oscillatory properties of mammahan central nervous system in vitro In L J Flndley and R Caplledo (Eds), Movement Disorders Tremor, Oxford Umversity Press. New York, N~, pp 165-182 Lhn~s, R R (1989) Electropbysiological properties of the olivocerebellar system, Exp Brain Res Ser., 17 201-208 Lhnfis, R R and Y Yarom (1988) Electrophyslology of mammalian inferior ohve neurons m wtro Different types of voltage-dependent Jomc conductances, J Physiol, 315 549-567 Longo, V G and M Massottl (1985) Effect of tremongemc agents on the cerebellum a review ot b~ochemical and electrophysJological data, Int Rev Neuroblol, 26 315-329 Narabayash~, H (1989) Stereotaxlc Vim thalamotomy for treatment of tremor, Eur Neurol, 29 (Suppl 1) 29-32 Ohye, C, T Hlrai, M Mlyazaki, T Shlbazakl and H_ NakaJJma (1982) Vim thalamotomy for the treatment of various kinds of tremor, Appl Neuropbysiol 45 275-280