L-Dopa infusion does not improve explicit sequence learning in Parkinson's disease

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Abstract

We have recently introduced a set of sequence learning tasks that emphasize explicit learning and target anticipation and involve the activation of frontal lobes. This type of learning is impaired even in the early stages of Parkinson's disease (PD). Studies on the effects of L-Dopa on cognitive symptoms of PD have yielded controversial results. To verify whether L-Dopa acutely improves explicit sequence learning, we tested six normal subjects and seven PD patients both off-drug and during L-Dopa infusion with two tasks: SEQ, a motor task with multiple demands, where a sequence had to be learned while reaching for a targets; VSEQ, a visual task where a sequence had to be learned by attending to a visual display without moving. Motor performance was assessed with simple motor tasks. L-Dopa improved motor scores and movement speed, but had no beneficial effect on either type of sequence learning.

Introduction

Cognitive changes, usually related to executive functions, working memory, attention, and visuomotor processing, are common even in early stages of Parkinson's disease (PD) and in non-demented PD patients [1], [2]. Cognitive deficits affect the ability to learn and retain motor tasks and may worsen the motor dysfunction of PD. Although the underlying pathophysiology remains unclear, the results of various studies attribute cognitive decline in PD to frontal lobe dysfunction [1], [2], [3], [4], [5], [6], [7], [8]. Animal and human studies have demonstrated that blocking dopaminergic receptors in the frontal lobe induces alterations in attentional resources allocation, working memory and elaboration of internal strategies, similarly to what is seen in PD [9], [10], [11], [12], [13].

The effects of antiparkinsonian therapies on cognitive dysfunction have been controversial. L-Dopa is a highly effective treatment for the motor deficits of PD. However, dopaminergic agents have been reported to produce contrasting effects on cognitive and related functions in both animal and patients’ studies. In fact, acute or chronic dopaminergic treatment may worsen frontal lobe function (for a review see: [14]).

We have recently used sequence-learning tasks in which instructions emphasized explicit learning, target anticipation and involve the activation of frontal lobes [15], [16]. With these tasks, normal subjects typically learn simple repeating sequences in 90 s or less, both when the sequence order is learned visually, without moving, and when learning occurs while reaching for targets. In patients with PD, sequence learning is generally slower for both tasks [15].

In this study, we evaluated the effects of constant infusion of L-Dopa on the learning of motor and visual sequences in patients with moderate to severe PD (Table 1).

Section snippets

Subjects

Patients were five men and two women (mean age: 58.4 years; range 55–66) with an established diagnosis of moderately severe PD. They were on long-term treatment with L-Dopa and a dopamine agonist, except for one patient who had milder PD and was treated with a combination of selegiline, a dopamine agonist, and anticholinergic agent. Controls were six normal subjects, five men and one woman (mean age: 56.9 years; range: 52–64). All subjects had scores greater than 27 on mini-mental status

UPDRS and neuropsychological tests

During L-Dopa infusion, UPDRS motor ratings decreased from 25.7 (±9.9 SE) to 16.6 (±6.7 SE) equivalent to 30.6% improvement (p=0.002). Overall, there was no significant effect of L-Dopa on cognitive function measured with neuropsychological tests. However, we found a greater number of false-positive errors in the recognition portion of HVLT test (p=0.019).

Motor tasks

In the patient group, durations of movements directed to predictable targets (CCW) were significantly reduced following L-Dopa infusion (Fig.

Discussion

Our study shows that in non-demented patients with moderate PD, intravenous dopaminergic treatment acutely improves both motor UPDRS scores and reaction and movement times of reaching movements. However, it fails to improve and, in some cases, further impairs explicit sequence learning and aspects of neuropsychological performance.

Prior clinical observations and many studies using a variety of motor tasks have demonstrated that L-Dopa greatly improves motor performance in PD. Only few studies

Acknowledgments

The authors wish to thank A. Hacking for valuable help in testing patients. Supported by Grants: NIH NS01961 and NPF (MFG); NS35069 and NS02101 (DE); AT000941 (ADR).

References (30)

  • F.P. Bowen et al.

    Parkinsonism: effects of levodopa treatment on concept formation

    Neurology

    (1975)
  • S.J. Lewis et al.

    Cognitive impairments in early Parkinson's disease are accompanied by reductions in activity in frontostriatal neural circuitry

    J Neurosci

    (2003)
  • A.M. Owen et al.

    Fronto-striatal cognitive deficits at different stages of Parkinson's disease

    Brain

    (1992)
  • U. Muller et al.

    D1- versus D2-receptor modulation of visuospatial working memory in humans

    J Neurosci

    (1998)
  • B.L. Murphy et al.

    Dopamine and spatial working memory in rats and monkeys: pharmacological reversal of stress-induced impairment

    J Neurosci

    (1996)
  • Cited by (0)

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