اختلالات در یادگیری طبقه بندی احتمالاتی دارویی در بیماری پارکینسون

In Parkinson's disease (PD), it is possible that tonic increase of dopamine associated with levodopa medication overshadows phasic release of dopamine, which is essential for learning. Thus while the motor symptoms of PD are improved with levodopa medication, learning would be disrupted. To test this hypothesis, we investigated the effect of levodopa medication on learning on the weather prediction task (WPT), which involves probabilistic classification learning. 11 PD patients and 13 matched controls completed 200 trials of the WPT, with the patients either on or off their usual levodopa medication. Consistent with prior studies, when PD patients were assessed on medication, overall WPT performance was significantly worse than controls. However, when these patients were studied following withdrawal from medication, overall performance was equivalent to controls, and significantly better than when on medication. The significant deterioration of learning on the WPT in PD patients when on compared to off medication supports the proposal that tonic increase of dopamine with dopaminergic medication masks phasic changes in dopamine release essential for learning. These results highlight the need for careful ‘titration’ of dopaminergic medication to produce the desired improvement of the motor symptoms without the associated detrimental effects on cognition and learning.

The WPT is a non-motor probabilistic classification task involving incremental learning over many trials considered to occur without any explicit knowledge (Knowlton, Squire, & Gluck, 1994). On each trial, participants are presented with a particular arrangement of tarot cards each with distinct patterns. On each trial, participants use the card arrangement to predict a binary outcome: whether the weather will be rainy or fine. Each of the four cards is independently associated with the two possible outcomes with a fixed probability, although participants are not explicitly informed about this. Knowlton, Mangels, and Squire (1996) reported a double dissociation on the WPT: for amnesics learning on the WPT was equivalent to healthy controls but they had no recollection of the stimuli or the learning episode; whereas patients with PD with striatal dysfunction were significantly impaired in learning on the WPT but nevertheless had good recognition of the stimuli and the testing episode. The specificity of deficits to striatal dysfunction was further confirmed by normal WPT learning by patients with frontal lesions (Knowlton, Mangels, et al., 1996) and those with cerebellar disease (Witt, Nuhsman, & Deuschl, 2002), and impaired learning by patients with Huntington's disease (Knowlton, Squire, et al., 1996). Other studies, however, have revealed learning deficits on the WPT and a parallel version of it in patients with bilateral hippocampal damage due to hypoxia (Hopkins et al., 2004 and Meeter et al., 2006). Consistent with the results of the studies in clinical populations, imaging work has demonstrated involvement of both the basal ganglia and medial temporal lobes (MTL) in learning during the WPT, although the time course of their involvement in learning is different and they show different sensitivity to distraction under dual task conditions, suggesting that the procedural and declarative memory systems compete or interact during learning on this task (Aron et al., 2004, Foerde et al., 2006, Poldrack et al., 2001, Poldrack et al., 1999 and Seger and Cincotta, 2006). On the basis of comparison of patterns of brain activation (Poldrack et al., 2001) and performance of PD patients in the standard feedback-based version of the WPT vs. a paired associate version; it has been further suggested that the feedback element of the WPT is the component that specifically engages the striatum (Poldrack et al., 2001 and Shohamy et al., 2004a); although such a selective impairment of learning on the feedback-based WPT relative to the paired associate WPT in PD has not been found in some studies, which reported deficits in learning in medicated PD patients relative to controls on both versions of the task (Wilkinson, Lagnado, Quallo, & Jahanshahi, 2008). An excellent review of research on the WPT has been recently provided by Shohamy, Myers, Kalanithi, and Gluck (2008). Dopamine deficiency is the primary hallmark of PD, which results from the loss of dopamine producing cells in the substantia nigra pars compacta which in turn leads to depleted levels of dopamine in the striatum (Hornykiewicz & Kish, 1984). Dopamine replacement therapy with levodopa or dopamine agonist medication remains the single most effective treatment for the motor symptoms of PD. In contrast, in PD levodopa medication has variable effects on cognitive function, improving some aspects of cognition including alternating word fluency (Gotham, Brown, & Marsden, 1988), working memory and cognitive sequencing (Cooper et al., 1992 and Shohamy et al., 2005) and task switching (Cools, Barker, Sahakian, & Robbins, 2001) but worsening other aspects of cognition including conditional associative learning (Gotham et al., 1988) probabilistic reversal learning (Cools et al., 2006, Cools et al., 2001 and Swainson et al., 2000) motor sequence learning (Feigin et al., 2003), incremental learning with feedback (Shohamy, Myers, Geghman, Sage, & Gluck, 2006) and multi-dimensional discrimination learning (Swainson et al., 2006). In light of this, in the present study, our aim was to test the hypothesis that medication impairs learning on the WPT in PD. We used a within-subject repeated measures design, and tested both PD patients on and off medication and matched controls with parallel versions of the WPT on two occasions.

We have demonstrated that in PD, learning on the WPT was significantly worse on than off medication. Our findings suggest that the impairment of learning observed in previous studies of WPT in PD may at least in part, be explained by the fact that PD patients have always been studied on medication (Knowlton et al., 1996a, Moody et al., 2004, Schmitt-Eliassen et al., 2007, Shohamy et al., 2004a, Shohamy et al., 2004b, Wilkinson et al., 2008 and Witt et al., 2002). These findings suggest that in PD the tonic increase of dopamine with dopaminergic medication may mask the phasic changes in dopamine release essential for incremental learning across trials. These results have implications for the medical management of PD and highlight the need for careful ‘titration’ of dopaminergic medication to produce the desired improvement of the motor symptoms without the associated detrimental effects on cognition and learning, particularly as impaired cognition negatively impacts on the quality of life of patients (Schrag, Jahanshahi, & Quinn, 2001) is associated with carer distress (Aarsland, Larsen, Karlsen, Lim, & Tandberg, 1999) and influences decisions about nursing home placement (Aarsland, Larsen, Tandberg, & Laake, 2000).