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J Neurol (2006) 253 : 186–193 DOI 10.1007/s00415-005-0951-4
Lidia Yágüez Herwig W. Lange Volker Hömberg
■ Abstract Background Parkinson’s disease (PD) and Huntington’s disease (HD) patients have difficulties executing sequential movements. Attention control and Received: 27 July 2004 Received in revised form: 16 May 2005 Accepted: 23 May 2005 Published online: 27 July 2005
Dr. L. Yágüez () PO77 Dept. of Psychology Henry Wellcome Building Institute of Psychiatry De Crespigny Park Denmark Hill London SE5 8AF, UK Tel.: +44-(0)207/848-0761 Fax: +44-(0)207/848-5006 E-Mail:
[email protected] H. W. Lange, MD · V. Hömberg, MD Neurological Therapy Center Heinrich-Heine University Düsseldorf, Germany
ORIGINAL COMMUNICATION
Differential effect of Huntington’s and Parkinson’s diseases in programming motor sequences of varied lengths
short-term memory probably play an important role in programming sequential movements. To investigate the contribution of these cognitive factors to programming and executing visuomotor sequences in HD and PD patients a computerized version of the Corsi Block Tapping-Test was employed. Methods the performance of 11 patients with early stage PD, 11 HD patients with borderline to mild caudate atrophy and 20 healthy subjects was compared. The task was a reaction time task where targets were illuminated in groups of sequences increasing from 2 items to 5 items. Subjects reproduced the sequence (pressing the illuminated target) in the same order of appearance. Reaction Times and movement times were recorded. Results PD patients had increasing difficulties in programming and executing series greater than three components. HD
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Introduction Patients with Parkinson’s disease (PD) have difficulties in executing repetitive, simultaneous or sequential movements [1–4]. In particular, they have problems switching from one motor program to the next,such that the motor plan does not run smoothly. Therefore, according to Marsden [5] the greater the complexity of the task, the more impairment will be evident in PD patients. A number of studies gave support to this prediction [6–9]. However, Rafal et al. [10] found no deficit in
patients did not differ significantly from the controls, although they showed a tendency to lose accuracy in the longer series. Both patient groups did not differ in their attention span. Conclusions In PD although the spatial information may be well stored, they have difficulty accessing it when their attention is overloaded, leading to poor encoding and slow information processing. This process interferes with programming and execution of movement sequences. HD patients in the early stages of the illness seem to have more attention resources than PD patients, so that they start to show more problems in executing visuomotor sequences with longer movement sequences than PD patients. ■ Key words cognitive function · movement disorders · Parkinson’s disease · Huntington’s disease
programming motor sequences of three components in patients with PD, suggesting that deficits may only emerge with longer sequences. If the integrity of the basal ganglia is needed to retrieve and activate at the right time the motor programs contained in a motor plan for complex movements, then patients with Huntington’s disease (HD) should show similar difficulties to PD patients in programming and executing complex series of movements. There is indeed some evidence that HD patients also have difficulties in executing simultaneous and sequential two joint movements [11].Although Hallett & Khoshbin [12] found that
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the motor programs for simple movements were preserved in HD patients, these patients have indeed difficulties in initiating and executing voluntary movements [13] As in PD patients, HD patients are slower than controls when performing repetitive tapping movements [14] or in performing sequential arm movements [15]. Although the deficits appear similar to those found in PD patients, differences in the affected basal ganglia structures raise the question whether specific deficits will be revealed on more detailed assessment. However, very few studies have examined the performance of sequential movements in HD patients, or even contrasted their performance with that of the PD patients.Agostino et al. [16] contrasted the motor performances of HD patients and PD patients on a sequential motor task. The results showed first, that the Movement Times (MTs) and the pauses between each movement of the two patient groups were slower than those of the control subjects. However, as the execution of the sequences progressed, the MTs of the PD patients for the segments lengthened. This was not found in the control group or in the HD patients. Therefore, although the HD patients were in general slower than the control subjects, they showed the same pattern of performance. In additional to the above motor aspects of programming movement sequences, in the preliminary phase of programming sequences short-term memory probably plays an important role. Surprisingly, there is little knowledge about the specific role of short-term spatial memory in programming motor sequences. There is no consistent evidence for short-term memory deficits in PD. In most studies, the immediate digit span [17–18] and immediate spatial span [19] have not been found to be impaired. Therefore another possible explanation could be that while the information may be well stored and available, they may have difficulties in accessing it to control attention processes [20–21]. In contrast to PD, some studies [22–24] have shown that patients with HD indeed show deficits in verbal as well as in spatial shortterm memory. To investigate whether HD patients and PD patients show similar or different patterns of programming and executing visuomotor sequences in relation to spatial short-term memory, a computerized version of the Corsi Block-Tapping-Test was employed in this study. The ability to reproduce verbal and visuospatial sequences with less of a motor component was also examined, as a means of determining the critical cognitive components of the motor task.
Methods To screen for dementia and to establish that the intelligence level of the patients was sufficient to understand and follow correctly the instructions two intelligence tests were administered: Mehrfachwahlwortschatztest (MWT-B; [25]), measuring verbal IQ, and Set-I of
the Raven’s Advanced Progressive Matrices (APM-Set I [26]). The verbal and spatial memory spans (digit span forwards and Corsi Block Tapping Test [27] forwards) were measured in all patients. ■ Apparatus The equipment consisted of a Siemens PCD-2 computer fitted with a 2 8 Bit parallel interface card. A specially designed software program controlled the stimulus presentation and the response recording with 1 ms resolution. The subject sat in an upright chair in front of a table on which a rectangular white board (surface 38 70 cm) was placed. On the board there were 8 raised square keys (6 6 2 cm). Each key contained a small red lamp, placed centrally 1.5 cm from the top edge of the key. One of the keys was situated centrally, 1 cm from the lower edge of the board. The remaining 7 keys were distributed in three horizontal lines. The central key was the “home” key, which had to be kept pressed between stimulus presentations. Each trial proceeded with the consecutive illumination of a set of the target keys situated above the home key. The program registered the time when the last target lamp went off. The subject responded by releasing the home key and pressing the target keys in the same order to their initial pattern of illumination. The time from when the last lamp of the series went off to the point when the home key was released was defined as the Reaction Time (RT). The time from release of the home key to the point when the first target key was pressed was defined as Movement Time 1 (MT1) and the time from the point when the first target key was pressed to the point when the second target key was pressed was defined as Movement Time 2 (MT2), and so on with the remaining target keys depending on the length of the series, that is, MT1 to MT5. After pressing the last target key the subject had to return to the home key and press it down. RTs, MTs and the positions were recorded for every trial. ■ Task It was explained that in the first series two of the lamps in front of them were going to be lit briefly, one after the other. As soon as the second lamp had been switched off, subjects had to release the home key and press the keys in the same order as they had been previously illuminated.After pressing down the last target key, they had to return to the home key, press it down and wait for the next trial. The same explanation was given for the next three series. The subjects completed 4 series each of 10 trials. The first series consisted of two target keys, the second series of three, the third series of four and the last series of five target keys. Each lamp was lit for 300 ms with a following delay of 700 ms. Each trial started 1000 ms after the subject had pressed the last target key and returned to the home key. For each series an extra position was added to the preceding sequence length, e. g.: Series1: 5, 3; 2, 4 etc; Series2: 5, 3, 1; 2, 4, 3 etc; Series3: 5, 3, 1, 7; 2, 4, 3, 5 etc. This system allowed for comparisons of RTs and MTs between blocks of trials of different lengths, which shared the same starting items. ■ Subjects Eleven patients (8 males) with HD participated in the study. Mean age: 47.0 years (SD: 10.4; range: 28–64). Average years of school education: 10.6 (SD: 2.1; range 8–13 years). Mean verbal IQ (MWT-B): 120.2 (SD: 11.2; range 100–136) and mean score on the APM-Set I:7.7 points (SD: 2.4; range 5–12). The mean digit span was 5.7 (range: 5–7) and mean spatial span: 5.3 (range 4–6). All HD patients had been clinically diagnosed by an experienced neurologist (H. W. L.) as having HD. A positive family history of HD was documented for all. All HD patients underwent quantitative neu-
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rological examination: The degree of choreic movement disorder was assessed with a clinical rating scale [28]. Eight patients had mild chorea, and 3 had moderate chorea. Functional ratings were obtained with a German adaptation of the Shoulson and Fahn scale [28] for the abilities of the patients in daily tasks (mean: 0.7, range 0.0–1.4). CT was carried out using a CGR ND 8000 Scanner in the University Clinic of Düsseldorf. A neuroradiologist, who had no access to the clinical and neuropsychological data, estimated the degree of cortical and subcortical atrophy. The distances between the left and right caudate nuclei (CC) and the inner table of skull (IT) were measured at the level of the interventricular foramen on the CC-line. The CC/IT was calculated and multiplied by 100, to obtain a percentage value of caudate atrophy. Five patients had borderline values (from 14 % –16 %), 5 had mild atrophy (between 16 % and 20 %) and one had moderate atrophy (between 20 % and 24 %). Cortical atrophy was estimated by measuring the width of the sulci in the frontal and occipito-parieto-temporal cortices. Two patients had no cortical atrophy, the rest had mild atrophy. Eleven PD patients (5 males) with average age of 71.0 years (SD: 7.7; range 54–81), participated in the study. Mean years of formal school education: 9.1 (SD: 1.0; range 8–10). Verbal IQ (MWT-B) was on average 103.5 (SD: 12.4; range 86–124) and mean APM-Set I score: 6.1 (SD: 1.2; range 4–8). Mean digit span was 5.6 (range: 4–7) and mean spatial span: 4.6 (range: 3–6). The duration of the disease since diagnosis ranged from 1 to 14 years (mean: 5.8; SD: 4.1). Stage of severity was measured with the Hoehn & Yahr scale. Four patients were classified in stage I, the reminder were in stage II. All patients were tested during their normal medication cycle, i. e. on-phase. The control sample consisted of 20 healthy volunteers (9 males) ranging in age from 30 to 73 (mean: 44.5, SD: 12.0). Some were spouses of the PD and HD patients, while the remainders were recruited from visitors to and staff of the NTC. Mean digit span was 6.2 (range: 5–8) and mean spatial span: 6.2 (range: 4–8) Because PD often has a later onset than HD, it was not possible to match the three groups exactly for age. The mean age of the healthy control subjects did not differ significantly from the mean age of the HD patients (t = 0.59, d. f. 29, p = 0.586). However, the PD patients were significantly older than the CG (t = 6.64, d. f. 29, p = 0.000) and HD patients (t = 6.24, d. f. 20, p = 0.000). Therefore, to control for possible age effects, age was always entered as a covariate in the MANOVAs. The study was performed in accordance with the ethical standards of the 1964 Declaration of Helsinki.
Results ■ Digit span and spatial span There were no significant differences between the three groups in relation to the digit span. There was, however, a significant group effect in relation to the spatial span (F(2,36) = 7.48, p = 0.002). PD patients had a significantly (p = 0.002) lower spatial span than the CG. There were no significant differences between the CG and HD patients or between the HD and PD patients.
■ Effects of Series Length upon RTs There was no significant Group main effect or a significant interaction effect Group Series. However, there was a significant Series main effect (F(3,117) = 14.93, p = 0.000). Age did not appear as a significant covariate in this analysis. As can be seen in Fig. 1, the three groups increased their RTs with Series length.
■ Data analysis Error trials were eliminated. RTs and MTs were analysed on an individual basis, extracting the medians for each subject for each series. Means of medians were calculated for each group. To analyse the effect of series length upon the RTs, a 3 Groups (CG vs. PD vs. HD) 4 Series (Series2 vs. Series3 vs. Series4 vs. Series5) repeated-measures MANOVA design with age as covariate and planned contrast was calculated. Post hoc tests were used to check significant effects. The analysis of the effects of series length upon the MTs were carried out in two steps: First, MT1 and MT2 of all four series were analysed in a 3 Groups (CG vs. PD vs. HD) 2 MTs (MT1 vs. MT2) 4 series (Series2 vs. Series3 vs. Series4 vs. Series5) repeated measures MANOVA design with age as a covariate and planned contrasts. Second, the effects of the longest series, were analysed in a 3 Groups (CG vs. PD vs. HD) 5 MTs repeated measures MANOVA design with age as a covariate and with planned contrasts. Post hoc tests were used to check significant effects.
Fig. 1 Reaction Times (time from stimulus onset to lifting the “Home Key”) for all series and for the three Groups. PD Parkinson’s disease; HD Huntington’s disease
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■ Effects of Series length upon the first two MTs of all series Age was not a significant covariate in this analysis. There were significant Group, Series, and MT main effects. There was no significant interaction Group Series, but MT interacted significantly with Group and Series. There was a significant three way interaction effect Group Series MT (see Table 1). The group contrast was significant between CG and patients (p = 0.000) and between PD and HD (p = 0.000). PD patients showed prolonged MTs in all series compared with the CG and HD patients (see Fig. 2). Furthermore, MT2 tended to be prolonged in relation to MT1 in Table 1 Effects of Series Length upon the first two MTs of all series DF
F-value
P
MANOVA for Series 2 vs. series 3 vs. series 4 vs. Series 5 Group main effect 2.38 Series main effect 3.38 MT main effect 1.38 2.38 Group MT interaction effect 2.114 Series MT interaction effect 6.114 Group Series MT interaction effect
16.52 12.95 21.15 4.41 19.03 7.64
0.000 0.000 0.000 0.019 0.000 0.000
MANOVA for Series 2 vs. Series 3 Group main effect MT Main effect MT Series interaction effect
2.38 1.38 1.38
14.59 76.33 9.27
0.000 0.000 0.004
MANOVA for Series 4 vs. Series 5 Group main effect Series main effect MT Group Interaction effect Series MT Interaction effect Group MT Series Interaction effect
2.39 1.39 2.39 1.39 2.39
7.69 22.76 8.17 15.84 5.03
0.000 0.000 0.001 0.000 0.011
MT Movement Time; DF degrees of Freedom
Fig. 2 Movement Time 1 time from leaving the “Home Key” to pressing the first Key of every series. Movement Time 2 Time from leaving the first Key to pressing the second key of every series. PD Parkinson’s disease; HD Huntington’s disease. S 2 to S 5 Series 2 to Series 5.
the CG and HD in all series. This pattern was different for the PD group, in which the relation MT1 and MT2 seemed to be inverted in the two longer series of 4 and 5 components. Therefore, to further elucidate the threeway interaction effect, two repeated measures MANOVAs, with planned contrasts for the comparison of series 2 vs. Series 3 and Series 4 vs. Series 5 were calculated. First, the MANOVA for Series 2 vs. Series 3 showed significant Group and MT main effects. There was a significant interaction MT series indicating that MT2 was prolonged in the two series compared with MT1 and tended to decrease in Series3 in relation to Series2, whereas MT1 remained stable. There were no significant interactions with the groups. Thus, although the PD patients were slower than the CG (p = 0.002) and HD patients (p = 0.000), the 3 groups showed a proportionate decrease in movement time on Series 3 (see Table 1). The results for the comparison Series4 vs. Series5 showed, besides the Group and Series main effect, a significant contrast CG vs. patients (p = 0.000) and HD patients vs. PD patients (p = 0.000) and significant two-way interaction of MT with Group and Series. In this analysis MT was not a significant main effect and there was no significant interaction effect Series Group. However, there was a three-way interaction effect Series MT Group (see Table 1). Post- hoc tests showed that all three groups increased MT1 on Series5 in relation to Series4 (CG: t = 5.05, d. f. 19, p = 0.000; HD: t = 2.33, d. f. 10, p = 0.042 and PD: t = 2.67, d. f. 10, p = 0.024). In relation to MT2, however, only the CG (t = 3.13, d. f. 19, p = 0.006) and HD patients (t = 2.43, d. f. 10,p = 0.036) showed a significant increase in MT5 in series5 compared with Series4, whereas in the PD patients MT2 did not change significantly in Series 5.
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■ Analysis of MTs for Series 5
■ Relation between RTs and MTs of each series
The results yield a significant Group main effect (F(2,37) = 26.12, p = 0.000) and significant contrast CG vs. patients (p = 0.000) and HD patients vs. PD patients (p = 0.000).Age was not a significant covariant.As can be seen in Fig. 3, PD patients were slower than the Controls and HD patients. However, MT did not turn out to be a significant main effect, yet there was a significant interaction effect MT Group (F(8,148) = 2.63, p = 0.010). It can be seen from Fig. 3 that the MTs of the CG did not change significantly across the 5 components of the series. The two patient groups showed more fluctuations and in particular the PD group showed a tendency to decrease the MTs on the first three components of the series followed by an increase in MT in the two last components.
As can be seen in Fig. 4 in the CG the prolonged RTs were followed by a significant reduction of MT1 in all series and the same relation applies to the HD patients. However, in the PD there were no significant differences between the RTs and the following MT on any of the four series (see Table 2). Furthermore, the pattern of MTs in the CG was maintained systematically over the four series. The delays between each component of the sequence were regular and minimal. The HD patients also displayed this pattern, although the variations between the movement segments tended to be more accentuated showing increasing pauses between the movement segments. In the case of the PD patients, the movement pattern was no longer maintained. Only in Series2 and Series3 did the movement pattern of the PD patients show some similarities to the movement pattern of the CG and HD patients. In the following Series, the movement pattern was not only irregular, but also the MTs were prolonged with the length of the movement sequence.
■ Effects of series length upon accuracy Mean Number of Errors The results showed significant Group (F(2,39) = 9.31, p = 0.000) as well as Series main effects (F(3,117) = 52.23, p = 0.000), and significant interaction effect Group Series (F(6,117) = 5.33, p = 0.000). The three groups increased the number of errors with Series length. Post-hoc tests revealed that in Series2, there was no significant difference in the number of errors between the three groups. In the series with three components, the number of errors did not differ between the CG and HD patients, or between the HD and PD patients but the PD patients committed significantly more errors than the CG (p = 0.041). In the series with 4 components, the PD showed a disproportionate increase in errors in relation to the CG (p = 0.044) and the HD patients (p = 0.018), which continues in the last series of 5 errors. Thus is this series the PD patients showed significantly more errors than the CG (p = 0.001) Table 2 T-tests results: Reaction Times vs. Movement Time 1 of all series
Fig. 3 Movement Times for the five components of Series 5. PDParkinson’s disease; HD Huntington’s disease. MT1 to MT5 Movement Times 1 to Movement Times 5
Series S2 S3 S4 S5
Control Group
Huntington Group
Parkinson Group
t
d.f.
P
t
d.f.
P
t
d.f.
P
6.84 7.68 7.83 7.77
19 19 19 19
0.000 0.000 0.000 0.000
6.34 5.56 4.71 6.48
10 10 10 10
0.000 0.000 0.001 0.000
0.51 0.99 1.28 0.75
9 9 9 9
0.620 0.345 0.232 0.474
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Fig. 4 Summary of all the Reaction Times (RT) and Movement Times (MT) for all series and all groups. CG Control Group; PD Parkinson’s disease; HD Huntington’s disease
and HD patients (p = 0.047), whereas the HD patients and CG did not differ significantly.
Discussion Overall both patient groups were able to program and execute effectively sequences up to three components. Once this number was exceeded, PD patients showed a clear lost of accuracy. Thus, the results will be discussed in two parts: first the sequences in which accuracy was similar for the three groups, followed by the sequences in which there was a decline in accuracy. It was expected that the RTs would be prolonged in relation to sequence length, reflecting the time needed to select the motor programs as well as the time needed to assemble the appropriate sequence of motor programs. This was the case for the two patient groups and the controls; the three groups did indeed prolong their RTs with increasing sequence length. This result suggests that neither HD patients nor PD patients differed from controls at this stage of motor programming. However, if the motor plan were effectively programmed at this stage, it should facilitate the rapid execution of the following movement [29]. This was the case for the controls and the HD patients, but not for the PD patients. These results suggest that while the controls and HD patients were programming the series effectively before they initiated the first movement, the PD patients prob-
ably started the movement before the motor programs were properly assembled. This had an effect in the ensuing duration of the single movement components, which were in the PD patients slower than the HD patients and CG. Nevertheless, the PD patients showed the same pattern of movement indicating that the programming was still effective. Furthermore, the level of accuracy was fairly similar in the three groups. Once the number of targets increased above three, the PD patients slowed the movement components and had a significant lost of accuracy. Contrary to that the CG and HD patients had faster MTs. It should be noted that HD and PD patients did not differ in their visuospatial span, and on average both patient groups achieved spans greater than 5 components. Nevertheless, HD patients seemed also to lose accuracy and tended to prolong the MTs of the longest series. Probably with increased task complexity both patient groups had increased difficulties maintaining in the working memory the targets. However, since there was a distinct pattern in the performance of the two patient groups, it could be that the main difficulty in the PD patients was in the internal storage of the target sequence and the retrieval of this information. That is, the increase in errors in the longer sequences in the PD group could well be due to an impairment of retrieval from working memory due to the longer time needed for the series. Johnson et al. [30] showed that PD patients had longer visual inspection times than healthy subjects and
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suggested that inspection times could be a measure of speed-of-information processing. According to Johnson et al. [30] the deficits showed by PD patients in RT tasks may be due to deficits in speed of information processing. Speed of information processing is linked to the working memory capacity [31]. Hence, a faster rehearsal allows the maintenance of larger amounts of information in the memory buffer. Therefore, the present results suggest in line with Brown and Marsden [21] that in PD although the spatial information may be well stored, they have difficulties accessing it when their attention is overloaded. That is, due to their possible slower speed of information processing, an increase in information may slow down the rehearsal of the information in the working memory and thus the amount of information maintained in the memory buffer will be reduced or lost. This process may interfere with the programming of the movement sequences. Clearly, studies of PD and HD patients can only offer a restricted view of basal ganglia functions because the pathology of both disorders does not involve all parts of the basal ganglia circuits. In addition the slow evolution of the diseases may allow for the formation of adaptive
or compensatory mechanisms [32]. Even so, functional imaging studies in healthy subjects and PD patients support the central role of the basal ganglia, among others, in attention functions, in particular in the putamen [33–34]. Striatum and medial premotor cortex are involved in the control of sequential motor behaviour [35]. Jenkins et al. [36] found in a PET study of motor sequence learning that during the execution of new as well as learned sequences of key presses, the left putamen, but not the caudate nucleus, was activated. Playford et al. [37] found that PD patients showed an impaired activation of the left putamen.Moreover,Chudasama et al.[38] reported in rodents that disconnecting lesions of the medial prefrontal cortex and the subthalamic nucleus produced deficits in attention and slower response latencies. The authors of these studies argue that attention control relies on a corticosubthalamic interaction within the neural circuitry of the basal ganglia. Such results could explain to some extent the differences in performance between the HD and PD patients, since in the early stages of HD the basal ganglia structure mainly affected is the caudate nucleus [39–40] whereas in early PD the putamen is more affected [8].
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