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Chapter 34 Cerebellar somatotopic representation and cerebro-cerebellar interconnections in ataxic patients
C.I. dc Zceuw. P. Strata and J. Voogd (Eds.) R o g n s s in Bmin Research, Vol 114 CB 1997 Elsevier Science BV. All rights reserved.
CHAPTER 34
Cerebellar somatotopic representation and cerebro-cerebellar interconnections in ataxic patients K. Wessel*, M.F. Nitschke Department of Neumlogy, Medical University.RatzeburgerAllee 160,D-23538 Lube& Gennany
Introduction
The cerebellum is an important contributor to central neuronal control of motor behaviour. Although its role is well documented by the clinical deficits associated with brain disorders affecting cerebellar function, human lesion studies (Holmes, 1917) failed to identify distinct representations for different motor acts. In the first part of our work we examined whether the cerebellar representation of motor acts performed by different body parts is distinct and orderly in terms of a somatotopic motor representation in the cerebellum. We focused on the anterior lobe of the cerebellums and used simple self-paced motor paradigms such as unilateral extension and flexion of hand or foot. Assessment of task-related activation by functional mapping was based on high-resolution MRI (Frahm et al., 1993) specially sensitized to changes in cerebral blood oxygenation (functional MRI;fMRI) (Frahm et al., 1994). The second part of our work focused on cerebro-cerebellar interconnections in patients with ataxia. The important role of the cerebellum in motor control is made possible by cerebellar in-
*Correspondingauthor. Tel.: +49 451 5002485; fax: +49 451 5002489; e-mail: [email protected]
puts and outputs from sideloops of transcortical projection (Allen and Tsukahara, 1974, Eccles, 1979). Projections to the cerebellum come from the cerebral sensory-motor cortex including the premotor cortex (area 61, from the visual cortex, the vestibular system and the spinal cord. The targets of cerebellar adjustments and adaptations are the sensory motor cortex and related subcortical systems. Therefore, one could assume, that in patients with cerebellar disease the execution of movements would alter the function of different brain regions, particularly supratentorial cortical areas, due to the dysfunction of the cerebellum. A central position in these premotor systems is attributed to the premotor and supplementary motor (SMA)cortices, operating in parallel with the primary motor cortices. Kornhuber and Deecke (1965) found that self-paced voluntary movement is usually preceded by a negative EEG potential, termed the Bereitschaftspotential (BP). The early component of the BP reaches its maximum amplitude over the SMA and was thought to be a correlate of a willful preparation of movement. The steeper late component is lateralized to the hemisphere contralateral to the arm moving and can be distinguished for hand and foot movements (Deecke und Kornhuber 1978, Boschert et al., 1983). Using BP recordings we examined whether the function of cortical areas is changed in ataxic patients with cerebellar degen-
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eration, as compared to normal controls (Wessel et al., 1994). With the same hypothesis we performed studies using transcranial magnetic brain stimulation (TSM), since excitability of the motor cortex can be evaluated by this method. TMS, after an initial excitatory postsynaptic potential, results in inhibitory postsynaptic potentials, which can be measured as an involuntary pause in tonic elektromyographic (EMG) activity. Inhibitory neurons in the motor cortex may play the major role in the genesis of this postexcitatory inhibition (Roick et al., 1993). An influence of the cerebellum on the excitability of the primary motor cortex is made possible by a strong excitatory input from the cerebellum to the motor cortex through the ventro-lateral nucleus of the thalamus (Asanuma et al., 1983). The existence of these projections suggests that cerebellar motor deficits such as prolonged reaction times and slowness of movement may be related to an insufficient activation of descending pathways in the presence of cerebellar dysfunction. We therefore compared postexcitatory inhibition after TMS between patients with cerebellar degeneration and normal controls (Wessel et al., 1996). Whereas BP-recordings and TMS allow a high resolution in time, the domain of positron emission tomography (PET) studies is a high spatial resolution. PET of patients with cerebellar degeneration revealed significant hypometabolism in the cerebellar hemispheres, cerebellar vermis and brainstem, but the cerebral metabolic rate of glucose utilization at rest was normal for the thalamus and cerebral cortex (Gilman et al., 1988). The measurement of regional cerebral blood flow (rCBF) by PET has proved a powerful tool for mapping task-induced alteration in neuronal activity in the human brain. The demonstration of focal increases in rCBF in subjects performing motor tasks has provided new insights into the functional organization of voluntary movement (Roland et al., 1982; Fox et al., 1985). In our experiments we choose sequential finger movements as the motor paradigm for studying supratentorial changes in the adjusted rCBF of patients with cerebellar degeneration (Wessel et al., 1995).
Methods
Patients and control subjects
For the fMRI-study on somatotopic motor representation in the human cerebellum we investigated eight healthy, right-handed volunteers with a mean age of 28 years, who had no history of neurological illness. Similar healthy control subjects were also included for the BP-recordings, the TMS-study and the PET-study. In the latter three studies we compared results in normal controls with those of patients with cerebellar degeneration. Patients either suffered from autosomaldominant or idiopathic cerebellar ataxia, the diagnosis was made on the basis of the medical history, physical examination, neurological examination, laboratory tests to exclude other diseases and the findings on computed tomography scans or MRI-scans. For the PET-study and for the study using BP-recordings patients with noncerebellar signs (e.g. olivo-ponto-cerebellar atrophy) were carefully excluded.
Functional recording was based on dynamic acquisition of CBO-sensitive images (TR/TE/flip angle = 62.5 ms/30 ms/lO, measuring time 6 s, slice thickness 4 mm, in plane resolution 0.78 X 1.56 mm2 interpolated to 0.78 x 0.78 mm2 during image reconstruction) as described previously (Frahm et al. 1993, 1994). Each dynamic series comprised six cycles of task performance (18 s) and rest (36 s). Subjects were instructed to extend and flex hand or foot at the wrist or ankle unilaterally with a frequency of about 2 Hz.During the MRI examination, task execution was triggered by tactile or photic signals and controlled by on-line video-monitoring. Subjects wore ear plugs and had their heads positioned in a cap which was evacuated to immobilize the head comfortably in an individually moulded shape. Activation was evaluated from dynamic MRI series by correlating the signal intensity course of each pixel with
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a box-car reference waveform (Bandettini et al., 1993) shifted by one image (6 s) relative to the periodic stimulation protocol to account for hemodynamic latencies and rise times. Spatial filtering replaced each pixel (0.61 mm2) by a 3 X 3-weighted mean with its neighbours. Individual statistical analysis of resulting correlation maps included a rescaling of correlation coefficients to the percentile rank of the integral of an inferred distribution of ‘correlational noise’ (Kleinschmidt et al., 1995a). Thresholding was performed at a 99.95 percentile rank equivalent to an overall error probability of 0.05% yielding maximally 15 false positive pixels. A subsequent iteractive, neighbourhood analysis incorporated pixels exceeding the 95.0 percentile rank into the primary foci. Admitted pixels were colour-coded and superimposed onto the corresponding flowsensitized anatomical image.
BP-Re~ordings Subjects performed self-paced finger-movements (Keys Task). They had to press seven keys in a predefined order. The keys used were key 1-6 on the numeric pad on the keyboard of a microcomputer. The required order of key presses was the same in each of 45 trials. Subjects did not have to memorize the sequence, instead they were visually guided on the screen of the microcomputer. Subjects were instructed to prepare mentally for the movement before each sequence began anew and let passed at least 3 s from the end of one sequence until the beginning of the next sequence (Wessel et al., 1994). For the recordings we used sintered Ag/AgCl electrodes, fixed to the head at Fz, Pz, Oz, C3 and C4, at both mastoids, above and below the right eye (to control for vertical eye movements and blinks), the outer canthus of each eye (to control for horizontal eye movements), over the belly of the right flexor digitorum communis muscle, and over the tendon of this muscle near the wrist (to record EMG-activity). EEG was amplified and filtered by a Nihon- Kohden 4221 amplifier, with frequency
limits set to 0.016 Hz (10-s time constant) and 30 Hz. Impulses from the microcomputer triggered
EEG-data collection. EEG averages were digitally low-path filtered at 10 Hz and three parameters were defined in each subjects averages: (1) amplitude of NS1, (2) amplitude of NS2, and (3) onset latency of the BP. NS1 was defined as the mean amplitude 600-800 ms before movement onset against the base line (2800-3000 ms before movement onset) and NS2 as the difference between the peak amplitude and the amplitude of NS1 (see Fig. 1). Onset latency was indirectly measured by computing mean levels of consecutive 200 ms epochs and testing these levels for negative deviation from baseline. The 200 ms epoch in which the curve started significantly deviating from baseline was regarded as the group’s onset latency. Analysis of variance (ANOVAs) on these parameters were performed. TMS
Transcranial magnetic stimulation was performed using a Magstim 200 HP (Magstim Company) with a maximum output of 2.0 T. A circular coil was centered over the vertex. Motor evoked potentials were recorded from the first dorsal interosseus muscle on both sides. Postexcitatory inhibition after transcranial single stimulation (PI-S) was determined by using a stimulus intensity 1.5-fold above motor threshold while subjects sustained slight voluntary contraction of 10-20% of maximal isometric force. Duration of PI-S was defined as the time period from the end of MEP (onset of EMG suppression) to the reoccurrence of EMG background activity. Five recordings were superimposed and shortest PI-S was determined (see Fig. 3).
PET Positron emission tomography was performed with a Scanditronix (Uppsala, Sweden) PC 2048-15B machine. Modified autoradiographic technique
Fig. 1. Activation map (fMRI) delineating cerebellar responses to extension and flexions at the right wrist (red) and ankle (blue).
(Herscovitch et al., 1983; Raichle et al., 1983)was used to measure changes in rCBF. Images of rCBF were obtained by summing the activity during the 60-s period in which an increase in cerebral radioactivity was first detected after the intravenous bolus injection of 30 mCI of I5Olabelled water. Each subject had 10 scans, five at rest and live during the sequential finger movement task. Functional localization and assessment of task-related neuronal activation were determined by the generation of a statistical parametric map (SPM) (Friston et al., 1990, 1991).
The significance of the changes in rCBF was analyzed by a pixel-by-pixel analysis of covariance (ANCOVA) to remove the effects of differences in global cerebral blood flow, followed by planned linear comparisons of the adjusted mean images. For each group, there was one planned comparison between movement task and rest. An additional between-groups comparison assessed the difference of the change in rCBF due to the task. Statistical significance was determined by the ttest. The value of t for each pixel in each comparison was calculated and then transformed to a
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normal standard distribution ( Z values) (Wessel et al., 1995). Results In the NRI-study on the cerebellar somatotopic representation all subjects showed task-related increases of MRI-signal intensities within the ipsilateral cerebellum. Figure 1shows activation maps from a representative case in an axial section covering the anterior lobe of the cerebellum. Performing the hand task, the center of activation was located mainly in the ipsilateral intermediate part of the lateral extension of the culmen, Larsell lobules H IV-V (in red). Foot movements resulted in ipsilateral activation within the central lobe, Larsell lobules 11-111 (in blue). In all cases, the areas activated by foot movements were smaller and located anterior and medial relative to the hand area (for further details see Nitschke et al., 1996). The grand means of the BP-recordings are shown in Fig. 2 for the midline recordings. Comparing grand averages between controls and patients there were three significant differences. First the NS1-component (early BP) was larger in the patients than in the control group at central recording sights. Second the NS2- component (motor potential) was smaller in patients than in the control group. Third the BP started rising earlier in the patients. Significant t-values were obtained from 1.8 to 1.6 s before the first key press in the patients, in controls significant t-values were not obtained until 1.2-1.0 s before the first key press (for further details see Wessel et al., 1994). In the TMS-study 11 of 24 patients (84,6%) had a pathological prolonged central motor conduction time (CMCT). Clinically pyramidal tract involvement was only found in six patients. Ten of the 24 patients (41.7%) had a prolonged postexcitatory inhibition (PI-S). Figure 3 shows a representative example with recordings of a normal control person in A) and of a patient with cerebellar degeneration in B). Mean duration of pI-S
in the whole patient group compared to controls was significantly prolonged, mean PI-S in controls was 138.5 ms and in patients 199.3 ms. Increased postexcitatory inhibition times did not correlate with the severity of ataxia. An important finding was that in five patients with normal CMCT pathological prolonged PI-S results were found (for further details see Wessel et al., 1996). The PET images common to all patients and control subjects comprised 21 of the stereotaxically normalized planes (see Fig. 41, and included only the superior aspects of the cerebellum but extended to the upper parts of the cerebral cortex. With the right-hand finger movements both, patients and controls, had significant increases in the adjusted rCBF in the primary motor cortex (Ml) on the left side, the ventral premotor area (PMv) on the left side, the supplementary motor area (SMA), the cingulate motor area (CMA), the Putamen (PUT) and the lobus parietalis inferior (LPI) on both sides, and the cerebellum on the right side. The control subjects and patients were compared with regard to increases in the adjusted rCBF during moving versus rest (Fig. 4). The right cerebellum, left PMv, and prefrontal cortices and LPI on both sides were relatively more active in the control subjects (in red) than in the patients. The M1 on the left side, SMA and PUT bilaterally, but particularly on the left side, were relatively more active in patients (in blue) than in control subjects. The 2-values and coordinates of selected brain areas showing a significant between-groups difference are given in Table 1 (for further details see Wessel et al., 1995). Discussion
Our fMRI-findings strengthen the view of a somatotopic component in the organization of the anterior lobe of the human cerebellum. Cerebellar hand representation in the ipsilateral anterior lobe is in line with previous electrophysiological studies demonstrating activation of single Purkinje cells within lobules H IV-V during arm
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Keys task: midline data control group
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Fig. 2. Grand means of the potentials (Bereitschaftspotentials)in the Keys Task (see text). Recordings from Fz. Cz, Pz and Oz. Movement onset at 0 s.
movements in trained monkeys (Brooks and Thach, 1981). These findings are also in qualitative agreement with neuroimaging data by PET
(Fox et al., 1985; Colebatch et al., 1991) and, more recently, functional MRI (Bates et al., 1993; Cuenod et al., 1993; Ellermann et al., 1994). Our
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present study refines previous definitions of the activation pattern for hand movements in showing their predominantly medio-lateral distribution along the individual folia. This pattern of activation corresponds to the orientation of the parallel fibres in the cerebellar cortex that link Purkinje cells into long medio-laterally oriented beams which in turn project to the cerebellar nuclei (Thach et al., 1992). Foot movements resulted in ipsilateral activation within the central lobule, Larsell lobules 11-111. This agrees with electrophysiological studies in animals (Snider and Eldred, 1952). Although functional segregation in the human cerebellum with activation foci for upper and lower limbs was distinct and non-overlapping, this somatotopic component is not as precise as in the primary motor cortex (Kleinschmidt et al., 1995b). Our present findings support a cranio-caudal organization of large scale somatotopy in the anterior cerebellum. However, the observation that a precise sompatotopic axis or field remained hard to define as well as electrophysiological results from animals (for review see Ito, 1984) suggest that cerebellar coding of motor behaviour of different body parts is far more complex than by mere topic representation. Our further studies focused on cerebro-cerebellar interconnections in patients with ataxia. The BP-recordings demonstrate a changed function of sensory-motor cortices in patients with ataxia as compared to normal controls. The NS2component (Fig. 21, close to movement onset, whose peak is the highest negativity reached in scalp recordings, was first described as the motor potential by Deecke et al. (19691, probably representing neuronal activity in the motor cortex. Localisation and timing of the 'motor potential' suggest that it may represent the cortical cell fixing at the time of the motor command (Tarkka and Hallett, 1990). The finding of a reduced peak of NS2 amplitude in cerebellar patients agrees with results from animal experiments, showing that the primary motor cortex receives a strong excitatory input from the cerebellar efferent system through the ventro-lateral nucleus of the
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Fig. 3. Postexcitatory inhibition (PI-S) in the right first dorsal interomus muscle. (A) Recording of a control subject; five recordings superimposed, duration of pl-S, 138 ms. ,(B) Recording of a patient with cerebellar degeneration; prolonged duration of PI-S, 223 ms.
thalamus (Asanuma et al., 1983; Schell and Strick 1984; Wise and Strick 1984). The excitatory state of the motor cortex can be studied by TMS. An inhibitory action can be elicited by TMS, which appears directly after the motor evoked potential and can be measured by blockade of tonic voluntary EMG-activity (postex-
Fig. 4. Statistical parametric maps (PET)for the difference in increases of rCBF between control subjects (red and yellow) and patients with cerebellar degeneration (blue).
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TABLE 1 Z-values and coordinates of locations with the maximal differences in relative increases in regional cerebral blood flow (rCBF) during movement between controls and patients. Higher relative rCBF increases in controls in the upper part, higher relative rCBF increases in patients in the lower part. Z-value
Area
Higher rCBF increases during movement in controls CB (right) PMv (left)
3.14 3.53
Higher rCBF increases during movement in patients M1 (left) SMA PUT (right) PUT (left)
6.12 3.21 3.0 3.42
_______
Coordinates X (width)
Y (anteropost.)
Z (height)
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- 12
- 34
- 24 -6
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- 34 -4 + 30 - 30
+ 12 0
+ 24 + 56 +8 +8
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M1, primary motor cortex; PMv, ventral premotor area; SMA, supplementary motor area; PUT, putamen; CB, cerebellum.
citatory inhibition) (see Fig. 3). It is suggested that postexcitatory inhibition (PI-S) is generated in the primary motor cortex and that intracortical inhibitory interneurons may play the major role (Roick et al., 1993). Our finding of prolonged PI-S in patients with ataxia indicates enhanced inhibitory mechanisms in the motor cortex. Our finding of enhanced inhibitory mechanisms in ataxic patients is in agreement with the reduced amplitude of the motor potential (NS2) in BP-recordings in patients with cerebellar degeneration. A normal input from the cerebellum seems to be crucial for the generation of a motor potential (NS2) and for a normal excitatory state of the primary motor cortex. Under normal conditions the Purkinje cells are inhibitory upon the deep nuclei which are the source of the cerebellar outflow neurones. Presumably, the cerebellum exerts a tonic facilitatory effect on the motor cortex that is restrained to a certain extint by the Purkinje cells (Sasaki, 197g; Asanuma et al., 1983). Prolonged postexcitatory inhibition in approximately half of our patients indicates enhanced inhibitory mechanisms in the motor cortex in cerebellar degeneration. If postexcitatory inhibition is produced by an active process involving excitation of cortical interneurones, than our
findings can be interpreted with the hypothesis that with loss of Purkinje cells in cerebellar degeneration there is a release of the cerebellar nuclear cells from inhibition. This may lead to a transient facilitation of cortical inhibitory interneurones and consequently induce excessive cortical inhibition with prolongation of postexcitatory inhibition. Accordingly, with cerebellar degeneration Purkinje cell loss dominates Over nuclear cell loss (Greenfield, 1954; Koeppen and Turok, 1992). Our finding of enhancement of inhibitory mechanisms in the motor cortex and the reduced motor potential (NS2) in BP-recordings in patients with cerebellar degeneration must be contrasted with the convincing increase in regional cerebral blood flow (rCBF) in the primary motor cortex associated with movements in patients with cerebellar degeneration, as demonstrated in our PET-study (see Fig. 4). Apparently, reduced cortical excitability (enhanced inhibitory mechanisms) and reduced NS2 in BP-recordings do not necessarily result in decreased rCBF activation in patients’ primary motor cortex. No change in resting metabolism of the primary motor cortex was found in patients with cerebellar degeneration (Gilman et at., 1988; Wessel et al., 1995). Obviously, increased rCBF in primary
586
motor cortex only becomes manifest in activation studies, whereas stimulation experiments (TMS), evaluating postexcitatory inhibition, result in decreased motor cortex excitability. On the other hand, increased rCBF in the primary motor cortex associated with movement in patients with cerebellar degeneration could reflect increased activity of inhibitory interneurones, as might be concluded from the results of our TMS-study to occur in these patients. Our recordings of movement-related cortical potentials demonstrated also changes of early BP-components, which reach its maximum amplitude over the S M A (Deecke and Kornhuber 1978, Lang et al., 1990). The early component NS1 was increased in patients, whereas a decreased NS1 was found in patients with Parkinson disease (Dick et al., 1989). This contrast between patients with cerebellar degeneration and Parkinson’s disease can be explained by anatomical and physiological findings, showing that a major portion of basal ganglia output is directed to non-primary motor areas, in particular the S M A (Jurgens, 1984, Schell und Strick, 19841, whereas the S M A does not get a strong direct cerebellar projection (Eccles, 1979; Sasaki, 1979). The increased NS1 could be a result of the larger effort by which the cerebellar patients try to compensate for their motor deficits by a more extended cortical activation preceeding voluntary movements. This may also explain the finding of an earlier onset of the BP (Fig. 2). Our PET-study demonstrated, that the decreased activation of the cerebellum in our patients influenced the activity of the pyramidal and extrapyramidal motor system, probably using the strong projections from the cerebellum to various supratentorial motor areas via the thalamus (see Fig. 4). In this study, the PMv, which is probably analogous to the arcuate premotor area in the monkey (Dum and Strick, 1991), was significantly more activated in the control subjects than in patients. This cortical region is considered as part of the lateral premotor system (Goldberg, 1985) and receives a strong cerebellar input via thalamus. The reduced activation in the PMv in patients could be a consequence of a disturbed or
decreased cerebellar input. Thus, we hypothesize, that in patients with cerebellar degeneration the lateral premotor system is used to a lesser extent. Goldberg (1985) suggested that the S M A functions as important cortical region in the medial, bilaterally organized, premotor system. Our finding of strong increases of the rCBF in the S M A during movement both, in control subjects and patients, provides further evidence for the role of the Sh4A in planning and executing hand movements. Moreover, we found that the S M A activation during movement was significantly increased in the patients as compared to the controls. Beside the SMA, the putamen (PUT) showed a stronger activation during movement in patients also. We conclude therefore, that the medial premotor system is more heavily used in patients with cerebellar degeneration. Apparently, in patients with cerebellar dysfunction, a basal ganglia thalamo-cortical circuit and the S M A are more activated, perhaps to compensate for the cerebellar dysfunction. Both on anatomical grounds and on the basis of our results, it appears that the cerebellum facilitates the lateral motor system area much more than it does the medial areas such as the SMA. Summary
Different methods of functional neuroimaging were used for studying somatotopic encoding of function in the cerebellum and for investigating cerebro-cerebellar interconnections in patients with cerebellar degeneration. fMRI showed, that the center of activation for hand function was located in the intermediate hemispheric portion of Larsell lobules H IV-V.Foot movements activated areas medial and anterior to the corresponding hand areas within Larsell lobules 11-111. Changed function in motor cortices could be demonstrated in patients with cerebellar degeneration as compared to normal controls by recording movement-related cortical potentials (BP). In patients the motor potential was almost lacking and transcranial magnetic stimulation demonstrated enhancement of inhibitory mechanisms
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(prolonged postexcitatory inhibition) in the motor cortex. PET-findings suggested, that both effects are correlated to increased activity of inhibitory interneurons. Cerebellar patients showed increased activation in relation to movements in the SMA and basal ganglia and reduced activation in the cerebellum and lateral premotor areas. It could be speculated, that compensatory mechanisms are the reason for a stronger activation of the medial premotor system, including SMA, in patients with cerebellar degeneration. On the basis of our results it appears, that the cerebellum facilitates the lateral premotor system areas much more than it does the medial areas. References Allen, G.J. and Tsukahara, N. (1974)Cerebro-cerebellar communication systems. Physiol. Reu., 54: 957-1006. Asanuma, C., Thach, W.T. and Jones, E.G. (1983)Distribution of cerebellar terminations and their relation to other afferent termination in the ventral lateral thalamic region of the monkey. Bmin Res., 286:237-265. Bandettini, P.A., Jesmanowin, A., Wong, E.C. and Hyde, J.S. (1993)Processing strategies for time-course data in functional MRI of the human brain. Ma@ Reson. Med., 30 161-173. Bates, S.R., Bandettini, P.A., Jesmanowicz, A., Estkoswki, L and Haughton. V.M (1993) Activation of the human cerebellum demonstrated by functional magnetic resonance imaging. Proceedings of the 12th Annual Meeting 1993 Aug 14-20;New York. Berkeley: Society of Magnetic Resonance in Medicine: 1420. Boxhert, J.. Hink, R.F. and Deecke, L. (1983) Finger movement Venus toe movement-related potentials: further evidence for supplementary motor area (SMA) participation prior to voluntary action. Exp. Bmin Res.. 5 2 73-80. Brooks, V.B. and Thach, W.T. (1981) Cerebellar control of posture and movement. In: Brookhart J.M., Mountcastle. V.B. and Brooks, V.B. (Eds.). Handbook of Physiology, Section I, Vol. 11, Pt. 2. Bethesda (MD): American Physiological Society: 877-946. Colebatch, J.G.,Deiber. M.P., Passingham, R.E., Friston, KJ. and Frackowiak, R.S.J. (1 991) Regional cerebral blood flow during voluntary arm and hand movements in human subjects. J. Neurophysiol, 65: 1392-1401. Cuenod, C.A., Zeffiro, T., Pannier, L, Posse, S.. Bonnerot, V. and Jezzard, P. et al. (1993) Functional imaging of the human cerebellum during finger movement with a conventional 1.5 T MRI scanner, Proceedings of the 12th Annual
Meeting: 1993 Aug 14-20;New York. Berkeley: Society of Magnectic Resonance in Medicine: 1421. Deecke. L. and Kornhuber, H.H. (1978)An electrical sign of participation of the mesial ‘supplementary’ motor cortex in human voluntary finger movement. Bmin Res., 159 473-476. Deecke, L and Scheid, P., Kornhuber, H.H. (1969) Distribution of readiness potential, premotion positivity, and motor potential of the human cerebral cortex preceding voluntary finger movements. f i p . Brain Res., 7: 158-168. Dick, J.P.R., Rothwell, J.C., Day, B.L., Cantello, R., Buruma, O., Giow, M., Benecke, R., Berardelli, A., Thompson, P.D. and Marsden, C.D. (1989) The Bereitschaftspotential is abnormal in Parkinson’s disease. Brain, 112: 223-244. Dum, R.P. and Strick, P.L. (1991) The origin of corticospinal projections from the premotor areas in the frontal lobe. J. Neumsci., 11: 667-689. Eccles, J.C. (1979) Introductory remarks. In: J. Massion and K. Sasaki (Eds.), Cerebro-cerebellar Intemctions, Elsevier, Amsterdam: 1-18. Ellerman, J.M., Flament, D., Kim, S.G.,Fu, Q.G., Merkle, H., Ebner, T.J. et al. (1994) Spatial patterns of functional activation of the cerebellum investigated using high field (4T) MRI. NMR Biomed., 7 63-68. Fox, P.T. Fox, J.M., Raichle, M.E. and Burde, R.M. (1985a) The role of cerebral cortex in the generation of voluntary saccades: a positron emission tomographic study. J. Neurophysiol.., 54: 348-369. Fox, P.T., Raichle, M.E. and Thach, W.T. (1985b) Functional mapping of the human cerebellum with positron emission tomography. hot. Nut1 Acad Sci., USA, 8 2 7462-1266. Frahm, J.. Merboldt, K.D. and Hanicke W. (1993) Functional MRI of human brain activation at high spatial resolution. Magn. Reson. Med., 29 139-144. Frahm, J., Merboldt, K.D.. Hanicke, W.,Kleinschmidt, A. and Boecker, H. (1994) Brain or vein-oxygenation or flow? On signal physiology in functional MRI of human brain activation. NMR Biomed., 7 45-53. Friston, K.J., Frith, C.D., Liddle. P.F., Dolan, R.J.. Lammertsma, A.A. and Frackowiak, R.S.J. (1990) The relationship between global and local changes in PET scans. J. Cereb. Blood Flow Metab., 10: 458-466. Friston, K.J., Frith, C.D., Liddle, P.F. and Frackowiak, R.S.J. (1991) Comparing functional (PET) images: the assessment of significant change. J. Cereb. Blood Flow Merab., 11: 690-699. Gilman, S.,Markel, D.S., Koeppe, R.A., Junck, L., Kluin, K.J., Gebarski, S.S. and Hichwa, R.D. (1988) Cerebellar and brainstem hypometabolism in olivopontocerebellar atrophy detected with positron emission tomography. A n n NeumL. 23: 223-230. Greenfield, J.G. (1954) The Spino-cerebellar Degenemrions. Blackwell, Oxford.
588 Goldberg, G. (1985) Supplementary motor area structure and function: Review and hypotheses. Eehau. Bmin Sci.. 8 567-615. Herscovitch. P., Markham, J. and Raichle, M.E. (1983) Brain blood flow measured with intravenous H2150. Theory and error analysis. J. Nucl. Med., 2 4 782-789. Holmes, G. (1917) The symptom of acute cerebellar injuries due to gunshot injuries. Emin, 40 461-535. Ito, M. (1984) The Cerebellum and Neural Control. Raven Press, New York. Jiirgens, U. (1984) The efferent and afferent connections of the supplementary motor area. Brain Res., 3M): 63-81. Kleinschmidt. A., Requardt, R., Merboldt, K.D. and Frahm, J. (1995a) On the use of temporal correlation coefficients for magnetic resonance mapping of functional brain activation. Individualized thresholds and spatial response delineation. Int. J. Imag. Sys. Technol., 6: 238-244. Kleinschmidt, A., Nitschke, M.F., Requardt, R. and Frahm, J. (1995b) How somatotopic is the human motor cortex hand area? Hum. Bmin Map. suppl. 1: 284. Koeppen, A.A. and Turok, D.I. (1992) The cerebellar cortex and the dentate nucleus in hereditary ataxia. In: A. Plaitakis (Ed.). Cerebellar Degenerations: Clinical Neumbiology, Kluwer Academic, Boston, pp 205-336. Kornhuber, H.H. and Deecke, L. (1965) Himpotentialanderungen bei Willkiirbewegungen und passiven Bewegungen des Menschen: Bereitschaftspotential und reafferente Potentiale. Ppigers Arch., 284: 1-17. Nitschke, M.F., Kleinschmidt. A,, Wessel, K. and Frahm, J. (1996) Somatotopic motor representation in the human anterior cerebellum. Brain, 119 1023-1029. Lang, W., Obrig. H., Lindinger, G.,Cheyne, D. and Deecke, L (1 990) Supplementary motor area activation while tapping bimanually different rhythms in musicians. Exp. Emin Res., 79: 504-514. Raichle, M.E., Martin, W.R.W., Herscovitch, P., Mintun, M.A. and Markham, J. (1983) Brain blood flow measured with intravenous H2150. 11. Implementation and validation. J. Nucl. Med., 24: 790-798. Roick, H., van Giesen, H.J. and Benecke. R. (1993) On the
origin of the postexcitatory inhibition seen after transcranial magnetic brain stimulation in awake human subjects. f i p . Emin Res.. 94: 489-498. Roland, P.E., Meyer. E., Shibasaki, T., Yamamoto, Y.L. and Thompson, C.J. (1982) Regional cerebral blood flow changes in cortex and basal ganglia during voluntary movements in normal human volunteers. J. Neurophysiol., 4 8 467-480. Sasaki, K. (1979) Cerebro-cerebellar interconnections in cats and monkeys. In: J. Massion and K. Sasaki (Eds.). Cerebmcerebellar lntemctions, Elsevier, Amsterdam, pp 105-124. Schell. P.R. and Strick, P.L. (1984) The origin of thalamic inputs to the arcuate premotor and supplementary motor areas. J. Neumsci., 4: 539-560. Snider, R.S. and Eldred, E. (1952) Cerebero-cerebellar relationships in the monkey. J. Neumphysiol., 15: 27-40. Tarkka, I.M. and Hallett, M. (1990) Cortical topography of premotor and motor potentials preceding self-paced, voluntary movement of dominant and nondominant hands. Electroenceph. Clin. Neumphysiol., 75: 36-43. Thach, W.T.,Goodkin, H.P. and Keating, J.G. (1992) The cerebellum and the adaptive coordination of movement. (Review). Annu. Rev. Neumsci., 15: 403-442. Wessel. K., Verleger. R.. Nazarenus, D., Vieregge, P. and Kompf, D. (1994) Movement-related cortical potentials preceding sequential and goal-directed finger and arm movements in patients with cerebellar atrophy. Electmenceph. Clin. Neumphysiol., 9 2 331-341. Wessel, K.. Zeffiro, T., Lou, J.-S., Toro, C. and Hallett, M. (1995) Regional cerebral blood flow during a self-paced sequential finger opposition task in patients with cerebellar degeneration. Emin, 118: 379-393. Wessel. K., Tegenthoff, M., Vorgerd, M., Otto, V., Nitschke, M.F. and Malin, J.-P. (1996) Enhancement of inhibitory mechanisms in the motor cortex of patients with cerebellar degeneration: a study with transcranial magnetic brain stimulation. Electmenceph. Clin. Neurophysiol.. 101: 273-280. Wise, S.P. and Strick, P.L. (1984) Anatomical and physiological organization of the non-primary motor cortex. Trends Neumsci., I 442-446.
CHAPTER 34
Cerebellar somatotopic representation and cerebro-cerebellar interconnections in ataxic patients K. Wessel*, M.F. Nitschke Department of Neumlogy, Medical University.RatzeburgerAllee 160,D-23538 Lube& Gennany
Introduction
The cerebellum is an important contributor to central neuronal control of motor behaviour. Although its role is well documented by the clinical deficits associated with brain disorders affecting cerebellar function, human lesion studies (Holmes, 1917) failed to identify distinct representations for different motor acts. In the first part of our work we examined whether the cerebellar representation of motor acts performed by different body parts is distinct and orderly in terms of a somatotopic motor representation in the cerebellum. We focused on the anterior lobe of the cerebellums and used simple self-paced motor paradigms such as unilateral extension and flexion of hand or foot. Assessment of task-related activation by functional mapping was based on high-resolution MRI (Frahm et al., 1993) specially sensitized to changes in cerebral blood oxygenation (functional MRI;fMRI) (Frahm et al., 1994). The second part of our work focused on cerebro-cerebellar interconnections in patients with ataxia. The important role of the cerebellum in motor control is made possible by cerebellar in-
*Correspondingauthor. Tel.: +49 451 5002485; fax: +49 451 5002489; e-mail: [email protected]
puts and outputs from sideloops of transcortical projection (Allen and Tsukahara, 1974, Eccles, 1979). Projections to the cerebellum come from the cerebral sensory-motor cortex including the premotor cortex (area 61, from the visual cortex, the vestibular system and the spinal cord. The targets of cerebellar adjustments and adaptations are the sensory motor cortex and related subcortical systems. Therefore, one could assume, that in patients with cerebellar disease the execution of movements would alter the function of different brain regions, particularly supratentorial cortical areas, due to the dysfunction of the cerebellum. A central position in these premotor systems is attributed to the premotor and supplementary motor (SMA)cortices, operating in parallel with the primary motor cortices. Kornhuber and Deecke (1965) found that self-paced voluntary movement is usually preceded by a negative EEG potential, termed the Bereitschaftspotential (BP). The early component of the BP reaches its maximum amplitude over the SMA and was thought to be a correlate of a willful preparation of movement. The steeper late component is lateralized to the hemisphere contralateral to the arm moving and can be distinguished for hand and foot movements (Deecke und Kornhuber 1978, Boschert et al., 1983). Using BP recordings we examined whether the function of cortical areas is changed in ataxic patients with cerebellar degen-
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eration, as compared to normal controls (Wessel et al., 1994). With the same hypothesis we performed studies using transcranial magnetic brain stimulation (TSM), since excitability of the motor cortex can be evaluated by this method. TMS, after an initial excitatory postsynaptic potential, results in inhibitory postsynaptic potentials, which can be measured as an involuntary pause in tonic elektromyographic (EMG) activity. Inhibitory neurons in the motor cortex may play the major role in the genesis of this postexcitatory inhibition (Roick et al., 1993). An influence of the cerebellum on the excitability of the primary motor cortex is made possible by a strong excitatory input from the cerebellum to the motor cortex through the ventro-lateral nucleus of the thalamus (Asanuma et al., 1983). The existence of these projections suggests that cerebellar motor deficits such as prolonged reaction times and slowness of movement may be related to an insufficient activation of descending pathways in the presence of cerebellar dysfunction. We therefore compared postexcitatory inhibition after TMS between patients with cerebellar degeneration and normal controls (Wessel et al., 1996). Whereas BP-recordings and TMS allow a high resolution in time, the domain of positron emission tomography (PET) studies is a high spatial resolution. PET of patients with cerebellar degeneration revealed significant hypometabolism in the cerebellar hemispheres, cerebellar vermis and brainstem, but the cerebral metabolic rate of glucose utilization at rest was normal for the thalamus and cerebral cortex (Gilman et al., 1988). The measurement of regional cerebral blood flow (rCBF) by PET has proved a powerful tool for mapping task-induced alteration in neuronal activity in the human brain. The demonstration of focal increases in rCBF in subjects performing motor tasks has provided new insights into the functional organization of voluntary movement (Roland et al., 1982; Fox et al., 1985). In our experiments we choose sequential finger movements as the motor paradigm for studying supratentorial changes in the adjusted rCBF of patients with cerebellar degeneration (Wessel et al., 1995).
Methods
Patients and control subjects
For the fMRI-study on somatotopic motor representation in the human cerebellum we investigated eight healthy, right-handed volunteers with a mean age of 28 years, who had no history of neurological illness. Similar healthy control subjects were also included for the BP-recordings, the TMS-study and the PET-study. In the latter three studies we compared results in normal controls with those of patients with cerebellar degeneration. Patients either suffered from autosomaldominant or idiopathic cerebellar ataxia, the diagnosis was made on the basis of the medical history, physical examination, neurological examination, laboratory tests to exclude other diseases and the findings on computed tomography scans or MRI-scans. For the PET-study and for the study using BP-recordings patients with noncerebellar signs (e.g. olivo-ponto-cerebellar atrophy) were carefully excluded.
Functional recording was based on dynamic acquisition of CBO-sensitive images (TR/TE/flip angle = 62.5 ms/30 ms/lO, measuring time 6 s, slice thickness 4 mm, in plane resolution 0.78 X 1.56 mm2 interpolated to 0.78 x 0.78 mm2 during image reconstruction) as described previously (Frahm et al. 1993, 1994). Each dynamic series comprised six cycles of task performance (18 s) and rest (36 s). Subjects were instructed to extend and flex hand or foot at the wrist or ankle unilaterally with a frequency of about 2 Hz.During the MRI examination, task execution was triggered by tactile or photic signals and controlled by on-line video-monitoring. Subjects wore ear plugs and had their heads positioned in a cap which was evacuated to immobilize the head comfortably in an individually moulded shape. Activation was evaluated from dynamic MRI series by correlating the signal intensity course of each pixel with
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a box-car reference waveform (Bandettini et al., 1993) shifted by one image (6 s) relative to the periodic stimulation protocol to account for hemodynamic latencies and rise times. Spatial filtering replaced each pixel (0.61 mm2) by a 3 X 3-weighted mean with its neighbours. Individual statistical analysis of resulting correlation maps included a rescaling of correlation coefficients to the percentile rank of the integral of an inferred distribution of ‘correlational noise’ (Kleinschmidt et al., 1995a). Thresholding was performed at a 99.95 percentile rank equivalent to an overall error probability of 0.05% yielding maximally 15 false positive pixels. A subsequent iteractive, neighbourhood analysis incorporated pixels exceeding the 95.0 percentile rank into the primary foci. Admitted pixels were colour-coded and superimposed onto the corresponding flowsensitized anatomical image.
BP-Re~ordings Subjects performed self-paced finger-movements (Keys Task). They had to press seven keys in a predefined order. The keys used were key 1-6 on the numeric pad on the keyboard of a microcomputer. The required order of key presses was the same in each of 45 trials. Subjects did not have to memorize the sequence, instead they were visually guided on the screen of the microcomputer. Subjects were instructed to prepare mentally for the movement before each sequence began anew and let passed at least 3 s from the end of one sequence until the beginning of the next sequence (Wessel et al., 1994). For the recordings we used sintered Ag/AgCl electrodes, fixed to the head at Fz, Pz, Oz, C3 and C4, at both mastoids, above and below the right eye (to control for vertical eye movements and blinks), the outer canthus of each eye (to control for horizontal eye movements), over the belly of the right flexor digitorum communis muscle, and over the tendon of this muscle near the wrist (to record EMG-activity). EEG was amplified and filtered by a Nihon- Kohden 4221 amplifier, with frequency
limits set to 0.016 Hz (10-s time constant) and 30 Hz. Impulses from the microcomputer triggered
EEG-data collection. EEG averages were digitally low-path filtered at 10 Hz and three parameters were defined in each subjects averages: (1) amplitude of NS1, (2) amplitude of NS2, and (3) onset latency of the BP. NS1 was defined as the mean amplitude 600-800 ms before movement onset against the base line (2800-3000 ms before movement onset) and NS2 as the difference between the peak amplitude and the amplitude of NS1 (see Fig. 1). Onset latency was indirectly measured by computing mean levels of consecutive 200 ms epochs and testing these levels for negative deviation from baseline. The 200 ms epoch in which the curve started significantly deviating from baseline was regarded as the group’s onset latency. Analysis of variance (ANOVAs) on these parameters were performed. TMS
Transcranial magnetic stimulation was performed using a Magstim 200 HP (Magstim Company) with a maximum output of 2.0 T. A circular coil was centered over the vertex. Motor evoked potentials were recorded from the first dorsal interosseus muscle on both sides. Postexcitatory inhibition after transcranial single stimulation (PI-S) was determined by using a stimulus intensity 1.5-fold above motor threshold while subjects sustained slight voluntary contraction of 10-20% of maximal isometric force. Duration of PI-S was defined as the time period from the end of MEP (onset of EMG suppression) to the reoccurrence of EMG background activity. Five recordings were superimposed and shortest PI-S was determined (see Fig. 3).
PET Positron emission tomography was performed with a Scanditronix (Uppsala, Sweden) PC 2048-15B machine. Modified autoradiographic technique
Fig. 1. Activation map (fMRI) delineating cerebellar responses to extension and flexions at the right wrist (red) and ankle (blue).
(Herscovitch et al., 1983; Raichle et al., 1983)was used to measure changes in rCBF. Images of rCBF were obtained by summing the activity during the 60-s period in which an increase in cerebral radioactivity was first detected after the intravenous bolus injection of 30 mCI of I5Olabelled water. Each subject had 10 scans, five at rest and live during the sequential finger movement task. Functional localization and assessment of task-related neuronal activation were determined by the generation of a statistical parametric map (SPM) (Friston et al., 1990, 1991).
The significance of the changes in rCBF was analyzed by a pixel-by-pixel analysis of covariance (ANCOVA) to remove the effects of differences in global cerebral blood flow, followed by planned linear comparisons of the adjusted mean images. For each group, there was one planned comparison between movement task and rest. An additional between-groups comparison assessed the difference of the change in rCBF due to the task. Statistical significance was determined by the ttest. The value of t for each pixel in each comparison was calculated and then transformed to a
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normal standard distribution ( Z values) (Wessel et al., 1995). Results In the NRI-study on the cerebellar somatotopic representation all subjects showed task-related increases of MRI-signal intensities within the ipsilateral cerebellum. Figure 1shows activation maps from a representative case in an axial section covering the anterior lobe of the cerebellum. Performing the hand task, the center of activation was located mainly in the ipsilateral intermediate part of the lateral extension of the culmen, Larsell lobules H IV-V (in red). Foot movements resulted in ipsilateral activation within the central lobe, Larsell lobules 11-111 (in blue). In all cases, the areas activated by foot movements were smaller and located anterior and medial relative to the hand area (for further details see Nitschke et al., 1996). The grand means of the BP-recordings are shown in Fig. 2 for the midline recordings. Comparing grand averages between controls and patients there were three significant differences. First the NS1-component (early BP) was larger in the patients than in the control group at central recording sights. Second the NS2- component (motor potential) was smaller in patients than in the control group. Third the BP started rising earlier in the patients. Significant t-values were obtained from 1.8 to 1.6 s before the first key press in the patients, in controls significant t-values were not obtained until 1.2-1.0 s before the first key press (for further details see Wessel et al., 1994). In the TMS-study 11 of 24 patients (84,6%) had a pathological prolonged central motor conduction time (CMCT). Clinically pyramidal tract involvement was only found in six patients. Ten of the 24 patients (41.7%) had a prolonged postexcitatory inhibition (PI-S). Figure 3 shows a representative example with recordings of a normal control person in A) and of a patient with cerebellar degeneration in B). Mean duration of pI-S
in the whole patient group compared to controls was significantly prolonged, mean PI-S in controls was 138.5 ms and in patients 199.3 ms. Increased postexcitatory inhibition times did not correlate with the severity of ataxia. An important finding was that in five patients with normal CMCT pathological prolonged PI-S results were found (for further details see Wessel et al., 1996). The PET images common to all patients and control subjects comprised 21 of the stereotaxically normalized planes (see Fig. 41, and included only the superior aspects of the cerebellum but extended to the upper parts of the cerebral cortex. With the right-hand finger movements both, patients and controls, had significant increases in the adjusted rCBF in the primary motor cortex (Ml) on the left side, the ventral premotor area (PMv) on the left side, the supplementary motor area (SMA), the cingulate motor area (CMA), the Putamen (PUT) and the lobus parietalis inferior (LPI) on both sides, and the cerebellum on the right side. The control subjects and patients were compared with regard to increases in the adjusted rCBF during moving versus rest (Fig. 4). The right cerebellum, left PMv, and prefrontal cortices and LPI on both sides were relatively more active in the control subjects (in red) than in the patients. The M1 on the left side, SMA and PUT bilaterally, but particularly on the left side, were relatively more active in patients (in blue) than in control subjects. The 2-values and coordinates of selected brain areas showing a significant between-groups difference are given in Table 1 (for further details see Wessel et al., 1995). Discussion
Our fMRI-findings strengthen the view of a somatotopic component in the organization of the anterior lobe of the human cerebellum. Cerebellar hand representation in the ipsilateral anterior lobe is in line with previous electrophysiological studies demonstrating activation of single Purkinje cells within lobules H IV-V during arm
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movements in trained monkeys (Brooks and Thach, 1981). These findings are also in qualitative agreement with neuroimaging data by PET
(Fox et al., 1985; Colebatch et al., 1991) and, more recently, functional MRI (Bates et al., 1993; Cuenod et al., 1993; Ellermann et al., 1994). Our
583
present study refines previous definitions of the activation pattern for hand movements in showing their predominantly medio-lateral distribution along the individual folia. This pattern of activation corresponds to the orientation of the parallel fibres in the cerebellar cortex that link Purkinje cells into long medio-laterally oriented beams which in turn project to the cerebellar nuclei (Thach et al., 1992). Foot movements resulted in ipsilateral activation within the central lobule, Larsell lobules 11-111. This agrees with electrophysiological studies in animals (Snider and Eldred, 1952). Although functional segregation in the human cerebellum with activation foci for upper and lower limbs was distinct and non-overlapping, this somatotopic component is not as precise as in the primary motor cortex (Kleinschmidt et al., 1995b). Our present findings support a cranio-caudal organization of large scale somatotopy in the anterior cerebellum. However, the observation that a precise sompatotopic axis or field remained hard to define as well as electrophysiological results from animals (for review see Ito, 1984) suggest that cerebellar coding of motor behaviour of different body parts is far more complex than by mere topic representation. Our further studies focused on cerebro-cerebellar interconnections in patients with ataxia. The BP-recordings demonstrate a changed function of sensory-motor cortices in patients with ataxia as compared to normal controls. The NS2component (Fig. 21, close to movement onset, whose peak is the highest negativity reached in scalp recordings, was first described as the motor potential by Deecke et al. (19691, probably representing neuronal activity in the motor cortex. Localisation and timing of the 'motor potential' suggest that it may represent the cortical cell fixing at the time of the motor command (Tarkka and Hallett, 1990). The finding of a reduced peak of NS2 amplitude in cerebellar patients agrees with results from animal experiments, showing that the primary motor cortex receives a strong excitatory input from the cerebellar efferent system through the ventro-lateral nucleus of the
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Fig. 3. Postexcitatory inhibition (PI-S) in the right first dorsal interomus muscle. (A) Recording of a control subject; five recordings superimposed, duration of pl-S, 138 ms. ,(B) Recording of a patient with cerebellar degeneration; prolonged duration of PI-S, 223 ms.
thalamus (Asanuma et al., 1983; Schell and Strick 1984; Wise and Strick 1984). The excitatory state of the motor cortex can be studied by TMS. An inhibitory action can be elicited by TMS, which appears directly after the motor evoked potential and can be measured by blockade of tonic voluntary EMG-activity (postex-
Fig. 4. Statistical parametric maps (PET)for the difference in increases of rCBF between control subjects (red and yellow) and patients with cerebellar degeneration (blue).
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TABLE 1 Z-values and coordinates of locations with the maximal differences in relative increases in regional cerebral blood flow (rCBF) during movement between controls and patients. Higher relative rCBF increases in controls in the upper part, higher relative rCBF increases in patients in the lower part. Z-value
Area
Higher rCBF increases during movement in controls CB (right) PMv (left)
3.14 3.53
Higher rCBF increases during movement in patients M1 (left) SMA PUT (right) PUT (left)
6.12 3.21 3.0 3.42
_______
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M1, primary motor cortex; PMv, ventral premotor area; SMA, supplementary motor area; PUT, putamen; CB, cerebellum.
citatory inhibition) (see Fig. 3). It is suggested that postexcitatory inhibition (PI-S) is generated in the primary motor cortex and that intracortical inhibitory interneurons may play the major role (Roick et al., 1993). Our finding of prolonged PI-S in patients with ataxia indicates enhanced inhibitory mechanisms in the motor cortex. Our finding of enhanced inhibitory mechanisms in ataxic patients is in agreement with the reduced amplitude of the motor potential (NS2) in BP-recordings in patients with cerebellar degeneration. A normal input from the cerebellum seems to be crucial for the generation of a motor potential (NS2) and for a normal excitatory state of the primary motor cortex. Under normal conditions the Purkinje cells are inhibitory upon the deep nuclei which are the source of the cerebellar outflow neurones. Presumably, the cerebellum exerts a tonic facilitatory effect on the motor cortex that is restrained to a certain extint by the Purkinje cells (Sasaki, 197g; Asanuma et al., 1983). Prolonged postexcitatory inhibition in approximately half of our patients indicates enhanced inhibitory mechanisms in the motor cortex in cerebellar degeneration. If postexcitatory inhibition is produced by an active process involving excitation of cortical interneurones, than our
findings can be interpreted with the hypothesis that with loss of Purkinje cells in cerebellar degeneration there is a release of the cerebellar nuclear cells from inhibition. This may lead to a transient facilitation of cortical inhibitory interneurones and consequently induce excessive cortical inhibition with prolongation of postexcitatory inhibition. Accordingly, with cerebellar degeneration Purkinje cell loss dominates Over nuclear cell loss (Greenfield, 1954; Koeppen and Turok, 1992). Our finding of enhancement of inhibitory mechanisms in the motor cortex and the reduced motor potential (NS2) in BP-recordings in patients with cerebellar degeneration must be contrasted with the convincing increase in regional cerebral blood flow (rCBF) in the primary motor cortex associated with movements in patients with cerebellar degeneration, as demonstrated in our PET-study (see Fig. 4). Apparently, reduced cortical excitability (enhanced inhibitory mechanisms) and reduced NS2 in BP-recordings do not necessarily result in decreased rCBF activation in patients’ primary motor cortex. No change in resting metabolism of the primary motor cortex was found in patients with cerebellar degeneration (Gilman et at., 1988; Wessel et al., 1995). Obviously, increased rCBF in primary
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motor cortex only becomes manifest in activation studies, whereas stimulation experiments (TMS), evaluating postexcitatory inhibition, result in decreased motor cortex excitability. On the other hand, increased rCBF in the primary motor cortex associated with movement in patients with cerebellar degeneration could reflect increased activity of inhibitory interneurones, as might be concluded from the results of our TMS-study to occur in these patients. Our recordings of movement-related cortical potentials demonstrated also changes of early BP-components, which reach its maximum amplitude over the S M A (Deecke and Kornhuber 1978, Lang et al., 1990). The early component NS1 was increased in patients, whereas a decreased NS1 was found in patients with Parkinson disease (Dick et al., 1989). This contrast between patients with cerebellar degeneration and Parkinson’s disease can be explained by anatomical and physiological findings, showing that a major portion of basal ganglia output is directed to non-primary motor areas, in particular the S M A (Jurgens, 1984, Schell und Strick, 19841, whereas the S M A does not get a strong direct cerebellar projection (Eccles, 1979; Sasaki, 1979). The increased NS1 could be a result of the larger effort by which the cerebellar patients try to compensate for their motor deficits by a more extended cortical activation preceeding voluntary movements. This may also explain the finding of an earlier onset of the BP (Fig. 2). Our PET-study demonstrated, that the decreased activation of the cerebellum in our patients influenced the activity of the pyramidal and extrapyramidal motor system, probably using the strong projections from the cerebellum to various supratentorial motor areas via the thalamus (see Fig. 4). In this study, the PMv, which is probably analogous to the arcuate premotor area in the monkey (Dum and Strick, 1991), was significantly more activated in the control subjects than in patients. This cortical region is considered as part of the lateral premotor system (Goldberg, 1985) and receives a strong cerebellar input via thalamus. The reduced activation in the PMv in patients could be a consequence of a disturbed or
decreased cerebellar input. Thus, we hypothesize, that in patients with cerebellar degeneration the lateral premotor system is used to a lesser extent. Goldberg (1985) suggested that the S M A functions as important cortical region in the medial, bilaterally organized, premotor system. Our finding of strong increases of the rCBF in the S M A during movement both, in control subjects and patients, provides further evidence for the role of the Sh4A in planning and executing hand movements. Moreover, we found that the S M A activation during movement was significantly increased in the patients as compared to the controls. Beside the SMA, the putamen (PUT) showed a stronger activation during movement in patients also. We conclude therefore, that the medial premotor system is more heavily used in patients with cerebellar degeneration. Apparently, in patients with cerebellar dysfunction, a basal ganglia thalamo-cortical circuit and the S M A are more activated, perhaps to compensate for the cerebellar dysfunction. Both on anatomical grounds and on the basis of our results, it appears that the cerebellum facilitates the lateral motor system area much more than it does the medial areas such as the SMA. Summary
Different methods of functional neuroimaging were used for studying somatotopic encoding of function in the cerebellum and for investigating cerebro-cerebellar interconnections in patients with cerebellar degeneration. fMRI showed, that the center of activation for hand function was located in the intermediate hemispheric portion of Larsell lobules H IV-V.Foot movements activated areas medial and anterior to the corresponding hand areas within Larsell lobules 11-111. Changed function in motor cortices could be demonstrated in patients with cerebellar degeneration as compared to normal controls by recording movement-related cortical potentials (BP). In patients the motor potential was almost lacking and transcranial magnetic stimulation demonstrated enhancement of inhibitory mechanisms
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