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Abstract
Objectives: The detection of dyskinesias-reduced-self-awareness (DRSA), in Parkinson’s disease (PD), was previously associated to executive and metacognitive deficits mainly due to dopaminergic overstimulation of mesocorticolimbic circuits. Response-inhibition dysfunction is often observed in PD. Apart from being engaged in response-inhibition tasks, the anterior cingulate cortex (ACC), is part of a functional system based on self-awareness and engaged across cognitive, affective and behavioural contexts. The purpose of the study was to examine the relationship between response-inhibition disabilities and DRSA using whole-brain event-related functional magnetic resonance imaging (fMRI), over the course of a specific executive task.Methods: Twenty-seven cognitively preserved idiopathic PD patients – presenting motor fluctuations and dyskinesias – were studied. They underwent a neurological and neuropsychological evaluation. The presence of DRSA was assessed using the Dyskinesias Subtracted-Index (DS-I). Cingulate functionality was evaluated with fMRI, while patients performed an ACC-sensitive GO-NoGO task. Association between blood oxygenation level dependent response over the whole-brain during the response-inhibition task and DS-I scores was investigated by regression analysis.Results: The presence of DRSA was associated with reduced functional recruitment in the bilateral ACC, bilateral anterior insular cortex and right dorsolateral prefrontal cortex (pFWE<0.05). Moreover, DS-I scores significantly correlated with percent errors on the NoGO condition (r = 0.491, pFWE = 0.009).Discussion: These preliminary findings add evidence to the relevant role of executive dysfunctions in DRSA pathogenesis beyond the effects of chronic dopaminergic treatment, with a key leading role played by ACC as part of a functionally impaired response-inhibition network. Imaging biomarkers for DRSA are important to be studied, especially when the neuropsychological assessment seems to be normal.
Highlights
Dyskinesias are disabling motor complications subsequent to prolonged use of dopaminergic agents in Parkinson’s disease (PD)
Subjects took part in the study only if: (i) they did not have a random on-off (ii) did not have early-morning and painful dystonia (iii) they did not show behavioural abnormalities such as major depression, dysthymia or alexithymia based on DSM-V criteria (American Psychiatric Association [APA], 2013) (iv) they did not have past and present neurological disorder and/or brain organic conditions (v) they were not taking drug therapies that could directly impact cognitive functioning, other than dopaminergic pharmacological replacement treatment; (vi) they had more than secondary school education (vii) they had a Mini Mental State Examination (MMSE) (Folstein et al, 1975) score≥27, in order to include only cognitively non-impaired subjects (Amanzio et al, 2010, 2014; Palermo et al, 2017)
Three patients withdrew from the study, while twenty-seven patients, with idiopathic PD, receiving levodopa treatment and presenting motor fluctuations, were enrolled
Summary
Dyskinesias are disabling motor complications subsequent to prolonged use of dopaminergic agents in Parkinson’s disease (PD). According to our hypothesis regarding the association between DRSA and executive dysfunction (Amanzio et al, 2010, 2014; Palermo et al, 2017), DRSA can arise when the comparator mechanism for “attentive-performance-monitoring” is damaged. In this case, PD patients may not be able to identify their motor symptoms, and dyskinesias do not achieve conscious awareness (Blakemore et al, 2001; Jenkinson et al, 2009). We have demonstrated the harmful role of dopaminergic pharmacological replacement treatment on the prefrontal-subcortical loops producing DRSA, which is linked to specific executive-metacognitive disabilities in terms of global monitoring, monitoring resolution, control sensitivity (Leritz et al, 2004; Amanzio et al, 2010), and the affective component of Theory of Mind (Palermo et al, 2017)
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