Procedural learning is impaired in Huntington's disease: Evidence from the serial reaction time task

Neuropsychologia, Vol. 29, No. 3, pp. 245-254, 1991 Printed in Great Britain.

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CQ2&3932/91 $3.oO+O.M) 1991 Pergamon Press plc

PROCEDURAL LEARNING IS IMPAIRED IN HUNTINGTON’S DISEASE: EVIDENCE FROM THE SERIAL REACTION TIME TASK DAVIDKNOPMAN*~-1 and MARY Jo NISSEN~ Departments of Neurology*

and Psychology,t

University

of Minnesota,

Minneapolis,

Minnesota,

U.S.A.

(Received 12 December 1989; accepted 18 September 1990) Abstract-The purpose of the study was to test the hypothesis that Huntington’s disease (HD) is associated with impairment of procedural learning. We identified 13 patients with mild to moderate HD whose manual performance was still sufficiently intact to assess learning on the serial reaction time (SRT) task. Twelve age-matched neurologically normal control subjects were studied as well. The SRT task was a four-choice reaction time task in which the stimuli followed a sequence (10 items in length) which repeated itself 10 times during each of the first four blocks of trials. During the fifth block of trials, the stimuli were random. Learning was manifested by a reduction in response latency over the first four blocks and an increase in response latency in the fifth (random) block. Learning in this task has been demonstrated in other amnesics of other etiologies. The HD patients were significantly impaired on sequence-specific learning, using the log-transformed reaction time data (P
INTRODUCTION THE HYPOTHESIS that the brain has separate learning systems has generated a great deal of

controversy [12,22,29]. The neuropsychological evidence is perhaps the most compelling for demonstrating multiple independent brain learning systems [22,29]. The typical amnesic has substantial difficulty in a declarative learning format, of which free recall would be a prototypical situation. Under other circumstances, some forms of learning are preserved in amnesics. The extent of preserved learning in amnesics spans a heterogeneous array of learning of various skills including reading words in mirror image [6, 151, performing sequential puzzles such as the Tower of Hanoi [S, 231, performing perceptual estimation [2, lo], performing the pursuit rotor task [9,11] or performing the serial reaction time task [13, 14, 171. The learning of skills without the conscious awareness of learning has been referred to as procedural learning [29]. Amnesics also show preservation of the function of priming, as in completing words stems with previously presented words [S, 24,26,28], which may be a distinct learning activity from procedural learning [29]. In several of these tasks [9-l 1,15,23], but not all [l 1,24,26], patients with Huntington’s SAddress correspondence to: David Knopman, MD, Minnesota Hospitals, Minneapolis, MN 55455, U.S.A. 245

Department

of Neurology,

Box 295, University

of

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D. KNOPMAN and M. J. NISSEN

disease (HD) may be impaired. In HD, the neuropathological changes are largely limited to the striatum, in particular the caudate nucleus [4, 301. The association of impaired procedural learning with HD has given rise to the claim [9,11,15], also supported by work in nonhuman primates [16], that the striatum plays a role in procedural learning. Dysfunction of procedural learning in the presence of specific neuropathological changes is also important evidence for favoring autonomy of procedural learning from declarative learning. In the present study, we sought to obtain additional evidence concerning the status of procedural learning in HD, using a model task developed in our laboratory [ 171. The serial reaction time (SRT) paradigm [17] provides a view of procedural learning that is complementary to those that have been previously studied [S, 6, 9, 11, 15, 231, but has additional advantages. The SRT task has received considerable validation as a measure of procedural learning in both experimental studies with normals and with brain damaged individuals [13,14,17,18,34]. It is a nonverbal four-choice reaction time task in which specific information is to be learned in the form of the sequence in which visual stimuli appear. The task is given under implicit learning conditions such that the subjects are not informed what is to be learned or that learning is involved in task execution. Sequence-specific learning and learning related to the execution of the choice reaction both occur in the SRT task. It thus differs from the pursuit rotor task [9,11], which does not involve the learning of item-specific information. The SRT task differs in many ways from the mirror reading paradigm [6, 151 in which itemspecific learning also occurs, in that the to-be-learned material in the SRT is non-verbal, limbmotor and inter- rather than intra-item. The SRT task requirements are thus distinct from previously studied tasks in which procedural learning has been demonstrated. Expansion of the domain in which procedural learning is well understood will lead towards more general models of the phenomenon of preserved learning in amnesics. METHODS Subjects Seventeen middle-aged HD patients were studied. Four patients were excluded because their motor function precluded satisfactory performance in the choice reaction time procedures. The remaining 13 had been diagnosed as having HD by other neurologists; the diagnosis was confirmed by history and examination by us. A positive family history of HD was documented for all. The duration of their disease since diagnosis ranged from 1 to 15 years (mean =4.4 years). They had 13.2 years of education, (range, l&l6 years). Agesand gender distribution are given in Table 1. The Mini-Mental State (MMS) exam f71 scores ranged from 22 to 30. Nine of the patients were on one or two medications for attempted control of chorea:th;ee on haloperidol, one on triazolam, twdon alprazolam, one on lorazepam, two on chlorazepate, one on clonazepam and one on desipramine. All of the HD patients also had quantitative neurological examinations [35]. Chorea was present in all, but was generally ofa low amplitude in the upper extremities. Slowness or arhythmicity of finger-thumb tapping was present in all patients. Slowness or arhythmicity of rapid alternating movements of the hands was present in most patients, but rapid alternating movements were normal in three. By functional ratings, the patients fell into stages II or III of the disease [27]. There were 21 neurologically normal individuals ranging in age from 30 to 50 who served as controls. Nine of the control subjects were later excluded because they had gained conscious awareness of the repeating sequence in the SRT task (see below). Since conscious awareness can facilitate performance [34], we excluded these nine, leaving a subset of 12 control subjects for subsequent analyses. The exclusion of the “aware” control subjects made the two groups more comparable as those normal subjects remaining did not bring declarative learning to bear on the task. Table 1 presents age and gender of the selected control subjects. They were better educated than the HD patients, having a mean educational level of 19 years, but were otherwise well matched for the HD patients. Procedures A neuropsychometric battery was given to patients and the controls. This included the logical memory and visual reproduction subtests of the Wechsler Memory Scale [31], the Block design subtest of the WAIS-R [32] and the Porteus mazes [20]. The scores of the 13 HD patients and the 12 unaware control subjects are given in Table 1.

PROCEDURAL

LEARNING

Table 1. Demographic

IN HUNTINGTON’S

and psychometric

Huntington’s patients (N= 13) X (SD) Age Sex (women/men) Education Mini-Mental State WMS logical memory (immediate recall) WMS visual reproduction (immediate recall) Porteus mazes (test age) WAIS-R block design (raw score)

241

DISEASE

data Normal

subjects*

Zb:’

41.6 (9.1) 5/8 13.2 26.6 (3.2) 3.9 (2.4)

40.7 (6.3)

4.1 (2.5)

12.1 (2.5)

10.9 (3.9) 12.0 (8.9)

17.2 (0.8) 33.8 (12.3)

517 19 n/a 9.7 (3.4)

*All group differences on psychometric tests were significant, P
D. KNOPMAN and M. J. NISSEN

248

the presence of sequence-specific learning within the first block. Note that the manner in which this ratio is calculated minimized the impact of the much faster RTs of the normal subjects. Finally, as measures of retention of the knowledge acquired, the RT in Block 6 was compared to Blocks 4 and 5. If sequence-specific knowledge was retained, then RTs should return in Block 6 to the same level as seen in Block 4, and be faster than Block 5.

RESULTS The HD patients clearly had cognitive impairment (Table 1). As a global measure of the cognitive impairment of the HD group, the mean MMS score of 26.6 indicated that this was a mildly impaired group. Only three of the HD patients scored below 26 on the MMS. However, on all of the standard psychometric tests, the HD patients were impaired compared to the age-matched control subjects. Since the groups differed with regard to educational background, the differences on some of these tasks may overestimate the HD patients’ level of cognitive dysfunction. On the SRT task, the normal subjects performed the task considerably faster than the HD patients (Fig. 1 and Table 2). The HD patients showed a greater reduction in RT over the first four blocks than the controls, but a smaller increase in RT between Blocks 4 and 5. Both

800

T T

700 600 I

2004

1

2

3

4

5

6

RPT

RPT

RPT

RPT

RAND

RPT

BLOCK Fig. 1. Mean reaction times for Huntington’s disease patients (N= 13) and control subjects (N= 12). Blocks 14 and Block 6 contained the repeating sequence of stimuli while in Block 5, the sequence of stimuli was random. Filled circles: control subjects. Open circles: Huntington’s patients. Error bars indicated one standard error above and below the mean.

groups showed a similar reduction in RT over the delay from Block 5 to 6. An ANOVA on all six blocks of data showed main effects of group [F (1,23)= 30.1, P=O.OOOl] and block [F(5, 115)= 12.4, P
PROCEDURAL

Table 2. Reaction

Block 1 2 3 4 5 6

Condition Repeat Repeat Repeat Repeat Random Delay repeat

LEARNING

IN HUNTINGTON’S

times and accuracy

Huntington’s RT Mean SD 759 665 643 588 650 556

for HD patients

and normal

82 86 90 89 87 90

controls Normal

disease % correct Mean SD

184 166 198 171 185 164

249

DISEASE

RT

20 11 8 12 10 8

Mean

SD

439 314 356 333 440 341

98 75 66 51 83 78

controls % correct Mean SD 96 97 91 96 95 97

2 2 2 4 4 3

(F< 1.0) but the data from Blocks 4 and 5 yielded a highly significant group x block interaction [F (1,23)= 10.8, P
-5po-:: -26 -1 BLOCK

p.

2t50

5Fo

:,5

1::

1::

lY$175

24 49 74 99 124 149 174 5 - BLOCK 4, RT DIFFERENCE (msec)

Fig. 2. Bargraph showing distribution of RT differences between Blocks 4 and 5 for the HD patients (open bars) and normal subjects (hatched bars). A negative value indicates failure to demonstrate sequence specific procedural learning.

performance in these five HD patients (“nonlearners”) suggested that they had failed to acquire sequence-specific knowledge. None of the 12 normal subjects showed this pattern. The least RT difference between Block 5 and Block 4 among the controls was 24 msec. Using this value as the cutpoint, the difference in proportions of nonlearners to learners between the two groups was significant (P < 0.04 by Fisher’s exact test). Thus, although the analysis was post hoc, there was a disproportionate number of HD patients who failed to demonstrate sequence-specific learning. The mean ratio for each group of sequence-specific to total procedural learning demonstrated that the HD group had a far lower ratio than the control group (0.38 vs 1.75).

250

D. KNOPMANand M. J. NISSEN

The HD patient who failed to show a decrease in RT over Blocks l-4 was excluded, but even with the exclusion of one nonlearner, the difference was significant (F= 7.02, P=O.O2), suggesting that the HD patients were deficient in sequence-specific learning. Another explanation of the low ratio of sequence-specific to total learning in the HD patients was that they were deficient in reaction-time-task performance, so that their performance over the first 400 trials involved relearning a motor act that the normal subjects had at their disposal immediately at the outset of the first block. The accuracy data (see below) would also support this latter explanation. Deficiencies in the reaction-time-task execution itself as well as sequence-specific learning probably both occurred in the HD patients. Over a 2C~60 min delay, both normal subjects and HD patients demonstrated savings in the sixth block. An ANOVA of the log-transformed data from Blocks 5 and 6 showed that the group x block interaction was not significant (F= 2.03, P> 0.10). The distribution of RT differences was very similar for the two subject groups. Thus, there were no differences in savings following SRT learning between the HD patients and the control subjects. Accuracy on the SRT task in the HD patients showed improvement in that it increased over Blocks 14 and then remained stable (Table 2). Since the normal subjects’ accuracies were very high, a comparison between the HD patients and controls had little meaning, except to point out that the HD patients as a group did not achieve the same level of accuracy after 600 trials that the normal subjects had achieved within the first 100 trials. Three of the five HD patients who failed to demonstrate sequence-specific procedural learning had very high accuracy by the third block of trials. To analyze the relationship between the measure of sequence-specific procedural learning (the Block 5 - Block 4 RT difference) and other patient characteristics, bivariate correlational analyses were carried out. No abnormality on the neurological examination including finger tapping, rapid alternating movements of the hands, or chorea involving the upper limbs was correlated with the measure of sequence-specific implicit learning. RT and accuracy in Block 1, both measures of manual motor function that were obviously more closely related than the neurological examination components to the SRT task, were also not correlated with the degree of sequence-specific learning. Neither immediate retention scores on the WMS logical memory subtest, the WMS visual reproduction subtest, the Porteus mazes nor prior educational achievement were correlated with degree of sequence-specific procedural learning. Performance on the MMS exam was also uncorrelated with degree of sequence-specific learning although the narrow range of performance on MMS (scores of 2CL30) may have made it difficult to demonstrate a relationship between MMS scores and SRT learning. We also carried out analyses comparing the eight learners with the five nonlearners on motor and psychometric performance and found no differences between the groups. Although the difference was not significant, the nonlearners were faster in the first block than the learners but committed more errors (see Table 3). Both patients receiving chlorazepate, two patients on haloperidol and one patient receiving clonazepam were among those patients who showed sequence-specific procedural learning, whereas the other three “learners” were on no medication. Of the patients who failed to show procedural learning only one was medication-free. On the Generate task, the HD patients performed at chance levels, implying that they did not acquire conscious awareness of the repeating sequence. The HD patients mean accuracy on the generate task was 34.4% while the controls’ mean accuracy was 45.6%. The HD group’s performance was only marginally worse than the unaware control subjects [F (1, 23)= 4.07, P= 0.0531. Individually, only one HD patient appeared to have conscious

PROCEDURAL

Table 3. Reaction

LEARNING

Learners

1 2 3 4 5 6

Condition Repeat Repeat Repeat Repeat Random Delay repeat

Mean

SD

806 655 653 558 674 526

187 150 184 134 171 89

(N= 8) Accuracy Mean SD 87 87 88 89 86 90

12 12 10 12 11 9

251

DISEASE

times (in msec) and accuracy (per cent correct) for Huntington’s sequence-specific learning vs those who did not

RT Block

IN HUNTINGTON’S

patients

Nonlearners RT Mean SD 684 680 627 636 612 603

170 207 240 226 219 251

who showed

(A’= 5) Accuracy Mean SD 73 84 91 88 88 90

28 9 5 10 9 6

awareness of part of the repeated sequence, with an accuracy of 60% in the generate task. On the other hand, among the initial pool of control subjects, nine (of 21) had gained sufficient declarative knowledge of the repeated sequence to achieve an accuracy score of over 70%. Thus, on the parallel declarative learning task, the control group was highly superior to the HD patients; however, in the unaware control subjects, generate task performance was not substantially better than the HD patients. DISCUSSION The HD patients in the present experiment performed in a heterogeneous manner, but, as a group, they were deficient in sequence-specific procedural learning compared to the control group. The control group was unaware of the repeating sequence and performed no better than the HD patients on the generate task, which assessed explicit knowledge of the repeating sequence. Therefore, the differences between the HD patients and the control group cannot be accounted for by a differential access to explicit knowledge on the part of the control group. Individually, a significant proportion of HD patients were deficient in acquiring sequencespecific procedural knowledge of the repeating sequence embedded with the SRT task. Almost all the HD patients showed large reductions in RT over the first four blocks indicative of reaction-time-task learning, but accuracy and RT generally did not reach the level of the normal subjects. At the same time, several HD patients had apparently normal procedural learning. Within the HD group, neither standard psychometric test scores nor features of the motor exam were correlated with procedural learning efficacy. We have administered an identical task to patients with Korsakoff’s syndrome [17] and with probable Alzheimer’s disease [13,14] and found that all of the Korsakoffs patients and most of the Alzheimer patients demonstrated preservation of sequence-specific procedural learning. There were, however, several Alzheimer patients who also failed to show procedural learning. Thus, the appearance of procedural learning failure was not unique to HD. With Alzheimer’s disease, though, the pathological changes are more widespread [ 19, 211, precluding a correlation of regional pathological changes in Alzheimer’s to the failure of procedural learning. In HD, however, such a correlation is possible. On the SRT task, even mild HD appeared to interfere with procedural learning. Our patients had mild declarative learning deficits, as is often the case early in the disease [3,5,11, 151. They scored considerably higher on psychometric tests than the Alzheimer patients in separate studies in our laboratory [13,14]. Our HD patients also had only mild to moderate deficits in limb-motor function (as demonstrated by their choice RT in all trial blocks of

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under 1000 msec) and had faster RT than AD patients in our other studies [13,14], whereas the HD patients in the pursuit rotor studies [9, 111 were slower than the AD patients. Our failure to show a correlation between disease severity could be due to the rather limited range of severity represented by our patient group. WILLINGHAM[33] has recently observed impaired sequence-specific learning on the SRT task in a group of mildly to moderately affected HD patients. The early striatal dysfunction that occurs in the disease [4, 291 was sufficient to impair procedural learning. The neuropathological changes of HD may not be uniform, however, as some of our patients performed at apparently normal levels. In other studies of procedural learning in HD patients, patient severity appeared to be correlated with the deficit in procedural learning. Two studies involving the Tower of Hanoi task [S, 231 showed that some mild HD patients performed at normal levels, while advanced HD patients were consistently impaired. A recently completed study on perceptual estimation gave the same findings: more advanced patients were impaired but milder patients showed the same prior exposure effects as normals [lo]. Learning in the pursuit rotor task [9,11] among HD patients was related to dementia severity, but not to severity of motor dysfunction. The HD patients included in the pursuit rotor studies of HEINDELet al. [9, 1l] had dementia rating scores that were equivalent to their Alzheimer patients, while in our study, no relationship between cognitive dysfunction and procedural learning efficacy was found. The performance of HD patients on learning tasks that are preserved in other amnesics may provide insights into the nature of procedural learning. The findings in HD vs more typical amnesics support the idea that tasks that involve skill learning are distinct from those that involve priming. Stem completion, which was unaffected in HD [ll, 24, 261, did not require skill acquisition. In contrast, all of the following tasks involved some form of skill learning and were impaired in HD: the pursuit rotor task [9,11], the Tower of Hanoi [S, 231, weight estimation [lo] and the SRT task. The task of mirror-reading, which was affected after the third day of testing in HD patients [lS], also did not involve limb-motor activity but did involve the learning of a skill. The pursuit rotor, by requiring the maintenance of accuracy of stylus positioning, may play into one of the basic disorders of motor control in HD, as may pushing one of four buttons rapidly (as in the SRT task) or manipulating the pieces in the Tower of Hanoi [S, 231. The Tower of Hanoi task may also involve skill acquisition at a more conceptual level, as may sequence-specific learning in the SRT task [34]. The perceptual estimation of object weight [2, lo] may appear to involve little coordination, but the interplay between proprioceptive stimuli and limb movement might actually require a considerable degree of skill acquisition. For an HD patient who cannot maintain a steady hand posture, the perception of object weight could be extremely difficult [lo]. These latter five tasks all have yielded similar results in HD as well as in other amnesics [2, 5, 9, 11, 13-15, 17, 231. Thus, procedural learning may involve motor, perceptual or conceptual skill acquisition, and all must depend heavily upon the integrity of the striatum. The striatum, particularly the caudate nucleus, is thought to play a role in nonmotor cognitive activity [l] as well as in the execution of skilled motor acts. Results from the SRT task may be particularly helpful in suggesting mechanisms for the interaction of striatal dysfunction and skill-demanding tasks. Attentional resource limitations, impaired feedback or interference with spatial memory are three plausible accounts. In normal subjects, it was possible to block procedural learning of the SRT task by requiring them to carry out a second task, such as tone counting, simultaneously [17]. Thus, a minimum level of attention was required for procedural learning in the SRT task to occur.

PROCEDURAL LEARNING IN HUNTINGTON’S DISEASE

253

Perhaps the effects of HD on the striatum results in a reduction in attentional resource. Along those same lines, normal SRT learning might depend upon proficiency of underlying motor performance. In the SRT task, changes in performance on the choice reaction time task can be distinguished from the sequence-specific learning. Inability on the part of HD patients to access the motor programs necessary for rapid execution of the reaction time task may have interfered with sequence-specific learning. In a separate study, we [25] found evidence for impaired access to previously learned motor programs, i.e. typical ideomotor apraxia, in many HD patients. The fact that HD patients had very slow RT initially but improved substantially over hundreds of trials was evidence for impairment of access to such simple motor programs as pushing a button in response to a stimulus. If each response was highly attention-demanding, perhaps the HD patients’ attentional capacities were utilized entirely by the execution of the underlying reaction time task. The HD patients might have been performing as if they were effectively in a dual task condition. On the other hand, Block 1 RT and accuracy were not correlated with procedural learning efficacy, which should have been the case if learning were predicated on basic skill in the reaction time task. A second explanation for the impairment of procedural learning in HD may relate to disturbed feedback generated by inaccuracy in responses. The HD patients’ inaccuracy may have impaired their ability to acquire knowledge at the same rate as the normal subjects. The impairment of proprioceptive feedback has also been raised as an explanation of HD patient’s impairment on perceptual estimation [lo]. In our study, the fact that three HD nonlearners had accuracies that were comparable to the normal subjects argued against a faulty feedback hypothesis. Third, the striatal involvement in HD may interrupt a dorsolateral prefrontal-caudate pathway that has been implicated in spatial memory [l]. To the extent that the repeating sequence in the SRT task could be encoded spatially, caudate pathology could interfere with sequence-specific learning in the SRT task. The lack of correlation between the tests of declarative visuospatial learning and sequence-specific learning in our HD patients spoke against a general relationship between spatial learning and SRT learning, although we had previously observed such a relationship in Alzheimer patients [13]. In our study, declarative learning (in the form of high accuracy on the Generate task) was absent in the SRT among the HD patients, while almost half of the original control group developed conscious awareness of the sequence. Declarative learning on standard psychometric tests was also impaired in the HD patients, so that in fact, both procedural and declarative learning were impaired. If procedural and declarative learning were autonomous functions, the pathological process in HD struck both. However, the key conclusion of our study and others [S, 9-11, 15,24, 261 was that procedural learning can be affected in HD patients whose declarative learning was not devastated and whose priming may be normal. Acknowledgements-The authors wish to thank Catherine Harman and Jeffrey Dusek for testing subjects and collating data. This work was supported by the Office of Naval Research contract No. NOOO14-86-K-0277to M. J. Nissen.

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