بررسی اثرات کاهش دوپامین نامتقارن بر حساسیت به محرک های پاداش و حالت تنفر در بیماری پارکینسون

The onset and progression of Parkinson's disease (PD) motor symptoms is generally asymmetric, reflecting differential extent of nigral pathology and resulting dopamine depletion in each of the hemispheres. Given the role of dopamine in processing rewarding and aversive events, and considering findings associating asymmetric neural activity with differential sensitivity to positive and negative stimuli, the current study examined the possibility that dopamine asymmetry in PD is related to differential approach and avoidance tendencies. An original task assessing and comparing sensitivity to positive and negative probabilistic feedback was administered to 29 right-handed participants with idiopathic PD, 16 with predominant right-side and 13 with predominant left-side motor symptoms, to compare the two groups. As dopamine replacement therapy (DRT) has shown different effects on reward and punishment processing, all participants were assessed in both off- and on-medication states. As predicted, when off medication, participants with relatively greater dopamine deficit in the left hemisphere minimized losses better than they increased gains, while those with a greater right hemisphere deficit showed a trend toward the opposite pattern. Medication reversed the relationship between gain and loss sensitivity in the left-hemisphere PD group, but not in the right-hemisphere group. Particularly in the left-hemisphere PD group, findings support the possibility that subcortical dopaminergic asymmetry is reflected in behaviorally-expressed approach and avoidance tendencies. Furthermore, the effects of DRT on approach and avoidance appear to interact with asymmetry, shedding light on previous conclusions regarding the role of dopamine in reinforcement processing.

Dopamine is central to neural processes underlying motivational control, with a widely accepted role in processing rewarding events and guiding goal-directed behavior, as well as known involvement in responding to aversive stimuli (Bromberg-Martin, Matsumoto, & Hikosaka, 2010). Accordingly, it has been proposed that the processing of positive and negative feedback and, more broadly, the relative tendency towards approach-related behaviors versus avoidance of aversive stimuli, is affected in populations in which the dopaminergic system is known to be compromised, among them patients with Parkinson's disease (PD). In PD, degeneration of dopaminergic cells in ventrolateral parts of the substantia nigra (SN) leads to depleted dopamine levels in striatal projection areas, particularly the posterior putamen (Bjorklund and Dunnett, 2007 and Hornykiewicz and Kish, 1984). Projections from the dorsal striatal area to cortical areas involved in motor control lead to the cardinal motor symptoms associated with PD. Loss of dopaminergic neurons in the ventral tegmental area and disruption of pathways from more ventral parts of the SN to the nucleus accumbens and caudate nucleus, which are associated with higher emotional and motivational functions (Middleton and Strick, 2000a and Middleton and Strick, 2000b), result in various non-motor manifestations of the disease (Bernal-Pacheco et al., 2012 and Cools, 2006). In this context, abnormalities in processing and learning from reinforcement have indeed been reported in PD (Bodi et al., 2010, Frank et al., 2004, Palminteri et al., 2009 and Shohamy et al., 2008). In the majority of individuals with PD, the onset of motor symptoms is asymmetric (Elbaz et al., 2005, Toth et al., 2004 and Uitti et al., 2005), presenting as more severe on either the left side or the right side of the body. While its etiology is unclear (Djaldetti, Ziv, & Melamed, 2006), this asymmetry is known to be associated with asymmetric degeneration of dopaminergic neurons in the substantia nigra (Kempster, Gibb, Stern, & Lees, 1989) and, more generally, with asymmetry in dopaminergic transmission in the striatum (Leenders et al., 1990 and Tatsch et al., 1997). Furthermore, it often persists throughout the progression of the disease (Djaletti et al., 2006). Davidson (2004) has proposed that differential sensitivity to positive and negative stimuli is associated with relatively asymmetric patterns of activation in anterior cortical regions, with several clinical and laboratory observations suggesting that left prefrontal cortex plays a more significant role in approach behavior, while right prefrontal cortex underlies withdrawal behavior and behavioral inhibition (Sutton & Davidson, 1997). As cortical asymmetries have been attributed to input from asymmetric subcortical neurochemical systems (Trevarthen, 1996), the dopaminergic system among them, it is suggested that dopamine asymmetry may play a role in modulating sensitivity to reward and punishment. The asymmetric dopamine depletion that leads to lateralized motor symptoms in PD presents a distinctive opportunity to examine this possibility. In a study examining approach and avoidance tendencies in PD, as expressed in the self-reported personality measures novelty seeking and harm avoidance, respectively, Tomer and Aharon-Peretz (2004) reported asymmetry-based effects, in line with Davidson's (2004) model. The aim of the current study was to determine whether this relationship between differential patterns of dopaminergic asymmetry and self-reported approach and avoidance tendencies would be expressed behaviorally, on a measure specifically designed to compare sensitivity to positive and negative feedback. Based on the aforementioned findings associating relatively greater left- and right-hemisphere activity with approach and withdrawal behavior, respectively, it was hypothesized that patients with a relatively greater degree of dopamine loss in the left-hemisphere (“left-hemisphere PD,” predominantly right-side motor symptoms) would be more sensitive to punishment than to reward, while the opposite would be true for patients with relatively greater dopamine loss in the right-hemisphere (“right-hemisphere PD,” predominantly left-side motor symptoms). It was further predicted that relative sensitivity to reward versus punishment would be correlated with a relative measure of motor asymmetry in the PD group as a whole. The dopamine-based medications used to treat PD have repeatedly been shown to affect reward and punishment processing in differential ways (Bodi et al., 2010, Frank et al., 2004, Palminteri et al., 2009 and van Wouwe et al., 2012), raising the possibility that medication interacts with asymmetry to determine approach and avoidance tendencies among asymmetric, medicated patients. Participants in the current study were thus assessed in both off-medication and on-medication states, such that the main and interactive effects of both asymmetry and medication could be evaluated. Predictions about possible interactions between medication and asymmetry can be considered in the context of the ‘dopamine overdose hypothesis’ (Cools, 2006 and Gotham et al., 1988). Attempting to explain the detrimental effects of systemically increased dopamine levels on some cognitive functions, this model suggests that dopaminergic medications such as l-dopa normalize dopamine levels in depleted areas, while increasing levels excessively in areas that are less affected (Cools et al., 2001 and Swainson et al., 2000). While this model was formulated based on evidence that striatal dopamine depletion in PD is expressed earlier and more significantly in dorsolateral areas than in more ventral areas (Kish, Shannak, & Hornykiewicz, 1988), the idea that performance on cognitive tasks may be disrupted by either reducing or increasing optimum dopamine levels can also be applicable with respect to asymmetry. Namely, when dopamine depletion is greater in one hemisphere than in the other, the addition of dopaminergic medications may ameliorate deficits in the more depleted hemisphere while excessively increasing dopamine levels in the other. Thus, medication is expected to alter the relationship between the two task conditions in each of the groups.