Voluntary actions can be fractionated in different phenomena: from the emergence of intentions and the ensuing motor plans and actions, to the anticipation and monitoring of their outcomes, to the appreciation of their congruency with intentions and to the eventual emergence of a sense of agency. It follows that motor intention and the sense of agency should occur at different stages in the normal generation of willed actions. Both these processes have been associated with a fronto-parietal motor network, but no study has investigated to what extent the two experiences can be dissociated for the brain regions involved. To this end, we assessed the PET/fMRI literature on agency and intentionality using a meta-analytic technique based on a hierarchical clustering algorithm. Beside a shared brain network involving the meso-frontal and prefrontal regions, the middle insula and subcortical structures, we found that motor intention and the sense of agency are functionally underpinned by separable sets of brain regions: an “intentionality network,” involving the rostral area of the mesial frontal cortex (middle cingulum and pre-supplementary motor area), the anterior insula and the parietal lobules, and a “self-agency network,” which involves the posterior areas of the mesial frontal cortex (the SMA proper), the posterior insula, the occipital lobe and the cerebellum. We were then able to confirm this functional organization by a subsequent seed-based fMRI resting-state functional connectivity analysis, with seeds derived from the intentionality/sense of agency specific clusters of the medial wall of the frontal lobe. Our results suggest the existence of a rostro-caudal gradient within the mesial frontal cortex, with the more anterior regions linked to the concept of motor intentionality and the brain areas located more posteriorly associated with the direct monitoring between the action and its outcome. This suggestion is reinforced by the association between the sense of agency and the activation of the occipital lobes, to suggest a direct comparison between the movement and its external (e.g., visual) consequences. The shared network may be important for the integration of intentionality and agency in a coherent appreciation of self-generated actions.

Levels of serum lactate dehydrogenase (LDH) are a recognized prognostic factor in malignant melanoma (MM). It is relevant to confirm its prognostic role in patients treated with targeted therapies [BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi)] and immunotherapy (IT). Furthermore, its role as a predictive marker in patients treated with these drugs had still not been investigated. We performed an electronic search for studies reporting information on overall survival (OS) or progression-free survival (PFS) according to LDH levels and on their predictive effect in patients treated with targeted therapies (BRAFi and MEKi) and IT. Data were pooled using hazard ratios (HRs) for OS and HRs for PFS according to a fixed-effect or a random-effect model. For predictive analysys, effect of new agents versus standard therapy was evaluated in LDH high population. A total of 71 publications were retrieved for a total of 16 159 patients. Overall, elevated LDH levels were associated with an HR for OS of 1.72 [95% confidence interval (CI): 1.6–1.85; P<0.0001]. Similarly, HR for PFS was 1.83 (95% CI: 1.53–2.2; P<0.0001). In the LDH elevated subgroup, new agents improved OS significantly (HR: 0.71; 95% CI: 0.62–0.82; P<0.0001) and PFS (HR: 0.63; 95% CI: 0.55–0.72; P<0.0001). In advanced MM treated with IT or BRAFi±MEKi, elevated LDH level at baseline represents a poor prognostic factor. However, patients with increased LDH levels and treated with these drugs gain significant benefits in terms of PFS and OS.

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With Motor imagery (MI), movements are mentally rehearsed without overt actions; this procedure has been adopted in motor rehabilitation, primarily in brain-damaged patients. Here we rather tested the clinical potentials of MI in purely orthopaedic patients who, by definition, should maximally benefit of mental exercises because of their intact brain. To this end we studied the recovery of gait after total knee arthroplasty and evaluated whether MI combined with physiotherapy could speed up the recovery of gait and even limit the occurrence of future falls. We studied 48 patients at the beginning and by the end of the post-surgery residential rehabilitation program: half of them completed a specific MI training supported by computerized visual stimulation (experimental group); the other half performed a nonmotoric cognitive training (control group). All patients also had standard physiotherapy. By the end of the rehabilitation, the experimental group showed a better recovery of gait and active knee flexionextension movements, and less pain. The number of falls or near falls after surgery was significantly lower in the experimental group. These results show that MI can improve gait abilities and limit future falls in orthopaedic patients, without collateral risks and with limited costs.

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