Some studies demonstrated specific changes in psychophysical measures of pain in Parkinson’s disease. A recent study by Tykocki et al. (2013) has demonstrated that pain threshold in patients with PD is significantly lower than pain threshold in non-parkinsonian patients.

Patients with central pain had lower thresholds for heat pain and laser pinprick than patients with no central pain or control subjects. These effects were attenuated with levodopa treatment (Schestatsky et al. 2007). Similarly, another study reported that L-DOPA increases the pain threshold in Parkinson’s disease as assessed by the RIII nociceptive flexion reflex (Gerdelat-Mas et al. 2007). Lower activation thresholds of spinal reflexes—reflecting spinal nociception—were also detected by Mylius et al. (2009). Moreover, increased spinal nociception as well as increased sensitivity toward various experimental stimuli was diminished by dopaminergic therapy (Brefel-Courbon et al. 2005; Tinazzi et al. 2008).

PD patients also showed facilitation of temporal summation, a process where the response to repeated painful stimuli is greater than to the administration of single stimulus of the same intensity. Temporal summation is frequently increased in chronic pain and is often considered as an indicator of central sensitization. PD patients are more sensitive than controls to the administration of repeated painful stimuli, suggesting supraspinal input alteration to pain modulatory systems (Perrotta et al. 2011). Moreover, when examining experimental pain sensitivity and spinal nociception, it was demonstrated that alterations of pain sensitivity worsen during the course of the disease (Mylius et al. 2009; 2011). As the authors highlighted (Mylius et al. 2011), when summarizing experimental pain studies on PD patients, alterations in different parts of the pain pathway were reported in the literature. In particular, at central level, increased pain processing was elicited by laser-evoked potentials (Brefel-Courbon et al. 2005; Tinazzi et al. 2008). At the peripheral level, nociceptor alterations were noticed, and at the spinal level, dorsal horn layer I involvement within the pathological process was observed (Braak et al. 2007; Nolano et al. 2008).

PET data demonstrated L-DOPA-dependent activation of the right insula and prefrontal left and left anterior cingulate cortices, suggesting pain processing alterations within the medial pain pathway (Brefel-Courbon et al. 2005). It is worth mentioning that medial pain system plays a crucial role in the motivational–affective and cognitive–evaluative components, in the memory of pain and in the autonomic–neuroendocrine pain-evoked responses.

As far as deep brain stimulation was concerned, it is interesting to report the results obtained in two different groups of Parkinson’s disease patients with or without neuropathic pain (Dellapina et al. 2012). The authors compared pain-induced cerebral activations during experimental nociceptive stimulations using H₂ ¹⁵O positron emission tomography in both deep brain stimulation off and on conditions. Correlation analyses were performed between clinical and neuroimaging results. Deep brain stimulation significantly increased subjective heat pain threshold and reduced pain-induced cerebral activity in the somatosensory cortex (BA 40) in patients with pain, whereas it had no effect in pain-free patients. There was a significant negative correlation in the deep brain stimulation OFF condition between pain threshold and pain-induced activity in the insula of patients who were pain-free but not in those who had pain. There was a significant positive correlation between deep brain stimulation-induced changes in pain threshold and in pain-induced cerebral activations in the primary somatosensory cortex and insula of painful patients only. The authors underline that subthalamic nuclei deep brain stimulation raised pain thresholds in Parkinson’s disease patients with pain and restored better functioning of the lateral discriminative pain system.

A neurocognitive approach may represent the best theoretical procedure to study pain in patients with PD. Most importantly, it highlights how pain is linked to brain pathology, particularly concerning focal lesions, motivational and emotional factors, and concomitant cognitive disturbances. Indeed, understanding pain in patients with different levels of cognitive impairment, by studying the neuropsychological and psychophysiological parameters, should represent an endeavor that has strong clinical implications. This is a very important issue to be taken into account as patients in mild to moderate stages of dementia may be unable to indicate pain perception through verbal or behavioral reports of pain. As dementia progresses to more severe stages, people lose the ability to communicate verbally, leaving them at a greater risk of experiencing untreated pain.

Importantly, a major aspect of future advances in pain research on PD patients will be to demonstrate linkages between behavior, brain, and bodily responses by combining research findings from neuropsychobiological and neuroimaging methods. Moreover, it would be extremely useful for the immediate clinical and prognostic implications to investigate pain from the very early prodromal stages of dementia. Unfortunately, up till now no study has addressed all these important issues while considering PD patients with MCI (PD-MCI).

The concept of MCI was initially suggested by Petersen et al. (1999) to detect cognitive changes in preclinical Alzheimer’s disease. The construct of MCI was applied to PD patients to identify a transitional state between a normal cognitive status to the presence of mild cognitive dysfunction by Janvin et al. (2006) and Caviness et al. (2007) that is not related to normal age decline. In particular, MCI is a condition that frequently occurs in PD even in the early stages, and it is associated with demographic and clinical factors such as age and disease duration. It does not significantly interfere with functional independence. MCI predicts that patients may develop dementia (Litvan et al. 2011), and over 80 % of them are at risk of PD-D (Hely et al. 2008). Early detection of PD-MCI has implications for prognosis and treatment; it is therefore important to assess the presence of MCI in order to identify those patients at risk of developing a form of dementia associated with PD (PD-D). It is also important to emphasize that the cognitive impairment was associated with a more rapid involution phenotype and with increased severity of symptoms in numerous studies. Recently, a task force commissioned by the Movement Disorders Society (MDS) has proposed and outlined the diagnostic criteria for the identification of MCI associated with PD (Emre et al. 2007; Litvan et al. 2012). These criteria use an operational scheme based on two assessment levels of cognitive profile. These two levels differ in the methods of evaluation and the level of diagnostic certainty and are characterized by an abbreviated assessment (level 1 criteria) or a comprehensive assessment (level 2 criteria), respectively.

It is being increasingly recognized that PD-MCI is heterogeneous (Litvan et al. 2011) and that many PD patients without dementia may show cognitive deficits not only in executive function due to dopaminergic degeneration but also in other domains including memory, visuospatial function, psychomotor speed, and attention (Marras et al. 2013; Broeders et al. 2013). The prototypical PD-MCI pattern is a predominant dysexecutive syndrome with visuospatial impairment, attentional deficits, and slowed processing speed (Taylor et al. 1986). When the pattern is atypical, it may reflect a greater burden of comorbid pathologies such as Alzheimer’s disease or cerebrovascular disease. Given this heterogeneity, clinicians require specific tools to assess the pattern and severity of cognitive impairment and to follow its progression (Marras et al. 2014). In particular, since executive dysfunction has been associated with declines in instrumental activities of daily living (IADL) that do not allow a person to live independently in the community (Cahn et al. 1998), specific assessment tools should be used at this level. In this direction, the relatively few studies that have investigated the connection between functional and cognitive abilities in pre-dementia stages of PD (Sabbagh et al. 2005, 2007; Shulman et al. 2008; Kulisevsky et al. 2013) have shown that when accurately measured, a certain degree of functional impairment in IADL can also be identified in PD-MCI subjects.

An aspect that should be considered when studying pain in PD patients is the important concept that dopaminergic treatment influences cognitive performance. An exemplification of this concerns the role of dopaminergic treatment on the executive functions (EFs). The findings of a systematic review and meta-analysis on PD patients supported the view that EF impairments are evident even at the beginning of the disease (Kudlicka et al. 2011). As the exact pattern of executive impairment remains unclear and the clinical significance still has to be clarified (Kudlicka et al. 2011), the research results show that PD patients performed poorly in cognitive flexibility and, more specifically, in set switching and inhibition tasks. Only the performance of these particular tasks was impaired, but the whole spectrum of executive abilities was not compromised (Goldman et al. 2013). The results obtained by the authors (Kudlicka et al. 2011) should be explained taking into account the different effects of dopaminergic stimulation on cognitive functions at the dorsolateral prefrontal level, on one hand, and on the medial prefrontal–ventral striatal circuitry (orbitofrontal and cingulated frontal–subcortical loops), on the other hand. In particular, it was demonstrated that dopaminergic stimulation improved EFs related to the cortical–subcortical network, from the dorsolateral prefrontal cortex (DLPFC) to the dorsal caudate nucleus, which is dopamine depleted. On the contrary, the same dopaminergic treatment impairs functions connected to the medial prefrontal–ventral striatal non-depleted circuit (Cools et al. 2001), such as on tasks of attentional set-shifting and response inhibition (Dirnberger and Jahanshahi 2013; Dujardin et al. 2001; Lewis et al. 2012; Muslimovic et al. 2005; Werheid et al. 2007; Amanzio et al. 2010, 2014). Importantly, while studying the different roles of dopamine on those different loops, motivational and reward behavior should be carefully taken into account.