داروهای دوپامینرژیک مخدوش کننده پردازش حواسپرتی شنوایی در بیماری پارکینسون

Parkinson's disease (PD) patients show signs of cognitive impairment, such as executive dysfunction, working memory problems and attentional disturbances, even in the early stages of the disease. Though motor symptoms of the disease are often successfully addressed by dopaminergic medication, it still remains unclear, how dopaminergic therapy affects cognitive function. The main objective of this study was to assess the effect of dopaminergic medication on visual and auditory attentional processing. 14 PD patients and 13 matched healthy controls performed a three-stimulus auditory and visual oddball task while their EEG was recorded. The patients performed the task twice, once on- and once off-medication. While the results showed no significant differences between PD patients and controls, they did reveal a significant increase in P3 amplitude on- vs. off-medication specific to processing of auditory distractors and no other stimuli. These results indicate significant effect of dopaminergic therapy on processing of distracting auditory stimuli. With a lack of between group differences the effect could reflect either 1) improved recruitment of attentional resources to auditory distractors; 2) reduced ability for cognitive inhibition of auditory distractors; 3) increased response to distractor stimuli resulting in impaired cognitive performance; or 4) hindered ability to discriminate between auditory distractors and targets. Further studies are needed to differentiate between these possibilities.

Parkinson's disease (PD) is a chronic, neurodegenerative disease characterized by loss of dopamine-producing cells in the Substantia Nigra pars compacta (SNpc) (Thenganatt & Jankovic, 2014). In addition to the motor symptoms (resting tremor, bradykinesia, rigidity, and in later stages, impaired postural reflexes), PD patients also show cognitive deficits even in the early stage of the disease (Dirnberger and Jahanshahi, 2013 and Ryterska et al., 2013). Commonly reported cognitive difficulties in early stage PD patients are executive dysfunction (e.g. difficulties in planning, set-shifting, conflict resolution, and reduced ability to perform tasks concurrently) (Dirnberger & Jahanshahi, 2013), deficits in working memory (WM) (Lee, Cowan, Vogel, Fernando, & Hackley, 2010), visuospatial function, and conditional associative learning (Kehagia, Barker, & Robbins, 2010). In addition to these, attentional difficulties are also very common in PD. Selective attention deficits (Zhou et al., 2012), problems with involuntary attention (Solis-Vivanco et al., 2011), attention set-shifting and flexibility deficits and disturbance of auditory attention (Bronnick, Nordby, Larsen, & Aarsland, 2010) have all been reported in PD patients. Therefore, a range of cognitive deficits, including attentional deficits, are common in early stage PD and have been directly related to the basic neuropathological changes in PD — decreased production of dopamine in SNpc, that leads to decreased concentration of dopamine in the striatum and consequently disturbed neuronal activity, primarily in the frontostriatal circuits including the associative circuit between the caudate and the dorsolateral prefrontal cortex (DLPFC) (Cools, 2006 and Gotham et al., 1988). Even though dopaminergic medication undoubtedly improves the motor symptoms of the disease, the effect of dopaminergic medication on cognition is diverse and often unpredictable. Namely, dopaminergic medication may either alleviate or deteriorate cognitive function, or have no effect on cognitive function (Briand et al., 2001, Bronnick et al., 2010, Cools, 2006, Cools, 2011, Cools et al., 2001, Gauntlett-Gilbert et al., 1999, Gotham et al., 1988, Kiesel et al., 2008, Sawada et al., 2012, Solis-Vivanco et al., 2011, Tachibana et al., 1992, Tinaz et al., 2011, Tombaugh, 2004 and Tsuchiya et al., 2000). It has been postulated that these contrasting effects of dopaminergic medication stem from an imbalance of dopamine in distinct regions of the striatum (Gotham et al., 1988). Research in healthy subjects (Cools & D'Esposito, 2011) has indicated that cognitive function depends on the optimal level of dopamine, which can be disrupted either by lack of or an overabundance of dopamine, resulting in an inverted-U-shape dependence of cognitive performance on dopamine level. In the early stages of PD the dopamine depletion is restricted to the dorsal striatum, leaving the ventral striatum relatively spared (Gotham et al., 1988 and Kish et al., 1988). This leads to a specific pattern of cognitive dysfunction dependent on specific neuronal circuits needed for the execution of the cognitive task tested. Relatedly, when dopaminergic medication is adjusted to ameliorate the depleted levels of dopamine in the dorsal striatum, it may overdose the ventral striatum, resulting in improvement of those symptoms and functions that depend on the dorsal, and deterioration of those that depend on the ventral striatum (Gotham et al., 1988). In summary, due to the way the dopaminergic system is affected in different parts of the striatum in early PD, the effect of dopaminergic medication on cognition in PD patients is complex and depends on many factors, such as the specific nature of the task, the engaged neuronal circuit, and the stage of the disease (Cools, 2006 and Gotham et al., 1988). Attention is one of the central concepts in neuropsychology and underlines most cognitive processes (Bocquillon et al., 2012). The involvement of the basal ganglia and dopamine in attention is complex (Bocquillon et al., 2012 and Knight et al., 1995). PD, characterized by dopamine depleted basal ganglia circuits, is a good model for studying the relation of attention to dopamine. In the study of human cognition a P3 cognitive event related potential (ERP) is probably the most used neural correlate of attention. Elicited when processing low-probability (rare) target stimuli (Polich, 2007), it has been shown to significantly correlate with attentional processes (Bledowski, Prvulovic, Goebel, Zanella, & Linden, 2004). The P3 has been robustly identified when actively or passively paying attention to rare target stimuli in a single (target only), double (rare target intermixed with frequent standard stimuli), or three (rare target intermixed with frequent standard and rare distractor stimuli) stimulus paradigms, in the auditory, visual, or somatosensory modality (Lugo et al., 2014, Polich, 2007 and Wronka et al., 2008). Interestingly, rare non-target, distractor stimuli also elicit a P3 response, which however, differs from the response to the target stimulus in its latency, amplitude and spatial distribution. The P3 response elicited by target stimuli (P3b) is characterized by a parietal maximum and a longer latency, compared to the P3 response elicited by distractor stimuli (P3a), which is more frontally distributed, has a shorter latency, and somewhat larger amplitude (Daffner, Mesulam, Holcomb, et al., 2000 and Daffner, Mesulam, Scinto, et al., 2000). P3a is assumed to reflect attentional reorientation and subsequent reallocation of attention to salient but irrelevant stimuli, and can be regarded as a marker of response inhibition processes in response to irrelevant stimuli. In contrast, P3b is thought to reflect components of attentional, WM, or event categorization processes that lead to decision making (Bledowski et al., 2004). Both P3a and P3b are traditionally described by their amplitude and latency; the former is considered to reflect the selective attention resources devoted to processing of the stimuli, whereas the latter is assumed to index the time necessary for controlled information processing (Kok, 2001). Empirical data from lesion and fMRI studies suggest different generators of P3a and P3b. For example, lesions of the prefrontal cortex decrease the response to distracting novel, but not to target stimuli in the three stimulus oddball paradigms (Knight, 1984 and Wascher et al., 2009). Similarly, patients with hippocampal damage can show a reduced response to distracting novel stimuli (Knight, 1996). In contrast, discrete lesions of the temporoparietal junction can result in reduced amplitude of both, P3a and P3b (Knight et al., 1989 and Nieuwenhuis et al., 2005). It seems that the orienting response to rare (target or distractor) stimuli, which reflects the immediate response to any change in the environment, activates frontal regions first; this signal is then transmitted towards the temporoparietal regions of the brain, possibly reflecting memory related processes (Polich, 2007). Indeed, imaging data show that both target and distractor stimuli activate the ventrolateral frontoparietal network, indicating a common mechanism for detection of rare events engaging bottom-up attentional processes (Bledowski et al., 2004). Presence of distractor stimuli further activates the dorsolateral frontoparietal network. This network is believed to be engaged in attentional switch from the target/standard discrimination and consequent attention allocation to the salient, rare distractor stimulus (Bledowski et al., 2004). In summary, it seems that different neural mechanisms, possibly regulated by different neurotransmitter systems, are involved in processing of distractor and target stimuli. Indeed, according to the dual-transmitter hypothesis (Polich, 2007 and Polich and Criado, 2006), frontally related P3a is likely mediated by dopaminergic activity, whereas P3b, which is related to parietotemporal brain regions, is probably mediated by noradrenaline activity. Furthermore, dopaminergic projections to the cortex are most abundant in frontal areas (Goldman-Rakic, 1998), whereas noradrenergic projections from locus coeruleus, are more diffusely distributed across the cortex, including the posterior and parietotemporal parts of the brain (Berridge and Waterhouse, 2003 and Nieuwenhuis et al., 2005). Therefore, it could be expected that different medications have different effects on P3a and P3b, depending on the mechanism of action. Specifically, dopaminergic medication should affect P3a rather than P3b, as the modulation of P3a seems to be more heavily dependent on the dopaminergic system. There are several lines of clinical evidence suggestive of the importance dopamine plays in the generation of the P3a/b response. For example, patients with restless leg syndrome, a condition marked by decreased dopaminergic state, show larger reduction of P3a compared to P3b amplitude (Choi, Ko, Lee, Jung, & Kim, 2012). A study by Takeshita and Ogura (1994) demonstrated that administration of a dopaminergic antagonist results in a differential effect depending on the baseline P3b amplitude: subjects with low P3b amplitude at baseline exhibited an increase of the amplitude after sulpiride (dopamine antagonist) administration; whereas conversely, subjects with high P3b at baseline exhibited an amplitude decrease after sulpiride administration. Despite important differences in the processes underlying P3a and P3b evoked potentials and their assumed dependence on dopamine, many of the studies of PD focused exclusively on the P3b potential evoked by the standard two-stimulus oddball paradigm. Some of these studies (Elwan et al., 1996, Graham et al., 1990, Green et al., 1996 and Karayanidis et al., 1995) found no differences between PD patients and healthy controls, whereas others reported reduced P3b amplitude (Koberskaia, Zenkov, and Iakhno (2003)), or prolonged P3b latency (Stanzione et al. (1998)) in PD patients compared to healthy controls. Additionally, Bodis-Wollner et al. (1995) have found that the P3b latencies in both auditory and visual oddball tasks significantly but differentially correlate with scores on cognitive tests. Specifically, P3b latency in the auditory oddball negatively correlated with basic visual perception, whereas P3b latency in the visual oddball task negatively correlated with tests of abstract reasoning. Of the studies that did differentiate between P3a and P3b, Tsuchiya et al. (2000) reported somewhat smaller P3b amplitudes in PD patients compared to healthy controls with more pronounced differences in P3a response to novel sounds, which was reduced, delayed and of a more posterior distribution in patients vs. controls. Similarly, in a recent study Solis-Vivanco et al. (2011) looked at a number of ERP correlates of involuntary attention, including mismatch negativity (MMN), P3a, and reorientation negativity (RON) in both medicated and non-medicated early PD patients compared to healthy controls. Whereas no group differences were identified in MMN amplitude, reflecting automatic detection of stimulus change, both P3a, reflecting distractor detection, and RON, reflecting reorienting towards task-relevant aspects of stimulation after distraction, were lower in medicated PD patients compared to non-medicated patients and healthy controls. There was no difference in latencies between different groups. In an earlier double blind placebo controlled study on healthy young participants with the dopaminergic (D2) antagonist haloperidol, Kahkonen et al. (2002) got similar results — haloperidol decreased the amplitude of P3a and RON, and did not change the amplitude of MMN. The latencies of all three components were also not affected by haloperidol. Even though different versions of the oddball task have been employed in the study of PD many times, there is, surprisingly, a lack of studies that would directly, in a repeated measures design, assess the effect of dopaminergic therapy on distractor and target processing, and their related P3a and P3b components in PD patients. This was the objective of the current study. Specifically, the study was designed to investigate the effect of dopaminergic medication on ERP measures of distractor and target processing in PD patients in a counterbalanced repeated measures study. Additionally, to better understand the nature of the effect in relation to potential restorative vs. overdose effects of dopaminergic therapy, patients both off and on medication, were also compared to an age-matched healthy control group. Based on previous literature we expected both P3a as well as P3b amplitudes to be reduced and latencies prolonged in PD patients off medication compared to healthy controls. Due to differences in processes underlying target and distractor processing, we expected a remediation of P3a with medication, as P3a, reflecting distractor processing, is to a larger extent dependent on dopamine-modulated prefrontal cortex. In other words, we expected higher P3a amplitude and shorter P3a latencies on medication compared to off medication in PD patients. Furthermore, we expected P3b, reflecting target processing that involves wider cortical areas modulated by other neurotransmitter systems (e.g. noradrenaline and acetylcholine), which are also affected in PD (Braak et al., 2003), to be less affected by the dopaminergic therapy. More specifically, we hypothesized that there would be no difference in either P3b amplitude or P3b latency in PD patients on medication compared to off medication. Finally, taking into account the assumption that the dopaminergic therapy results primarily in reconstitution of cognitive function related to P3a we expected lower P3b amplitude and longer P3b latency and no difference in P3a amplitude and latency in patients on medication compared to healthy subjects.

To our knowledge, this was the first repeated measures study of the effect of dopaminergic therapy on both P3a and P3b ERP correlates of cognitive processing in PD. The study revealed a differential effect of dopaminergic therapy on processing of irrelevant vs. target auditory stimuli and related brain systems. Though the study failed to provide more specific information about the nature of the effect, it revealed important specificity in the effect of dopaminergic medication on cognitive processing, underlying the need for further detailed studies of the effects of dopaminergic therapy on cognition in PD.