A novel neurocognitive approach for placebo analgesia in neurocognitive disorders

Neural correlates of placebo analgesia (PA) in patients with neurocognitive disorders have not yet been elucidated. The present study aimed to evaluate how and to what extent executive (dys)functions of the medial prefrontal cortex (MPFC) may be related to PA. To this end, twenty-three subjects complaining of different cognitive deficits (from mild cognitive impairment likely due to Alzheimer's disease to mild AD) were recruited. PA was investigated by a well-known experimental venipuncture pain paradigm (open versus hidden [O-H] application of lidocaine). Patients also underwent a comprehensive neuropsychological evaluation and a functional magnetic resonance imaging (fMRI) GO/No-GO task for eliciting selective activation of the MPFC. Selected neuropsychological variables were correlated to the OH-PA paradigm. The association between the fMRI response on the "No-GO" versus "GO" contrast and PA was investigated over the whole-brain by regression analysis. We showed the existence of a relationship between a lower PA and MPFC dysfunctions through the neuropsychological and fMRI assessment. A separate voxel-based morphometry (VBM) analysis controlled for possible influence of grey matter (GM) volume reduction on both fMRI results and PA. fMRI results were not directly affected by, and therefore independent of, disease-specific GM atrophy, which was indeed located more anteriorly within the rostral anterior cingulate and inversely correlated with PA. Our findings shed new light on the underestimated contribution of executive (dys)functions mediated by the MPFC (response-inhibition, self-monitoring and set-shifting abilities) in PA pathogenesis, with a special purely (i.e. independently from brain structural alterations) functional role played by the MCC. Results are discussed in terms of possible clinical relevance in the management of patients with neurocognitive disorders.