The Role of Ventromedial Prefrontal Cortex in Mental Time Travel and Mind Wandering

Recent research showed that a network of brain regions known as the Default Mode Network (DMN), including the ventromedial prefrontal cortex (vmPFC), is active when individuals remember the past, imagine the future, take the perspective of others, as well as during spontaneous cognition (mind wandering). The goal of this dissertation is to investigate whether the vmPFC plays a crucial role during DMN-related cognitive processes, such as MTT and mind wandering. Experiment 1 revealed that a damage to the vmPFC provokes the disruption of past and future MTT and a decreased ability to imagine future other-related episodes. vmPFC role extends to imagining events that are not self-relevant indicating that vmPFC is crucial for the imagination of complex experiences alternative to the current reality. In experiment 2, findings showed that a lesion to vmPFC disrupts the ability to construct complex atemporal scenarios. However, unlike the control groups, vmPFC patients had more difficulties in imagining future compared to fictitious experiences, suggesting that vmPFC is more critical for the simulation of future episodes. Experiment 3 revealed that these results are not explained by the disruption of non-episodic capabilities, such as narrative and working memory abilities. Furthermore, experiment 4 explored the effect of a lesion to vmPFC on the occurrence of mind wandering. A damage to the vmPFC provokes a decreased propensity to mind-wander, showing that vmPFC supports spontaneous cognition. Experiment 5 confirmed the involvement of the medial prefrontal cortex (mPFC) in supporting mind wandering. Using the transcranial direct current stimulation to inhibit the mPFC we could decrease the intensity of mind wandering in males. Together, these results point out the fundamental role of vmPFC in allowing human beings to escape the here and now, whether it occurs deliberately or spontaneously

Regenerative potential of the Bichat fat pad determined by the quantification of multilineage differentiating stress enduring cells

Published studies regarding Bichat fat pad focused, quite exclusively, on the implant of this adipose depot for different facial portions reconstruction. The regenerative components of Bichat fat pad were poorly investigated. The present study aimed to describe by an ultrastructural approach the Bichat fat pad, providing novel data at the ultrastructural and cellular level. This data sets improve the knowledge about the usefulness of the Bichat fat pad in regenerative and reconstructive surgery. Bichat fat pads were harvested form eight patients subjected to maxillofacial, dental and aesthetic surgeries. Biopsies were used for the isolation of mesenchymal cell compartment and for ultrastructural analysis. Respectively, Bichat fat pads were either digested and placed in culture for the characterization of mesenchymal stem cells (MSCs) or, were fixed in glutaraldehyde 2% and processed for transmission or scanning electron microscopy. Collected data showed very interesting features regarding the cellular composition of the Bichat fat pad and, in particular, experiments aimed to characterized the MSCs showed the presence of a sub-population of MSCs characterized by the expression of specific markers that allow to classify them as multilineage differentiating stress enduring cells.  This data set allows to collect novel information about regenerative potential of Bichat fat pad that could explain the success of its employment in reconstructive and regenerative medicine

Transcranial direct current stimulation of the medial prefrontal cortex dampens mind-wandering in men

Mind-wandering, the mind's capacity to stray from external events and generate task-unrelated thought, has been associated with activity in the brain default network. To date, little is understood about the contribution of individual nodes of this network to mind-wandering. Here, we investigated the role of medial prefrontal cortex (mPFC) in mind-wandering, by perturbing this region with transcranial direct current stimulation (tDCS). Young healthy participants performed a choice reaction time task both before and after receiving cathodal tDCS over mPFC, and had their thoughts periodically sampled. We found that tDCS over mPFC - but not occipital or sham tDCS - decreased the propensity to mind-wander. The tDCS-induced reduction in mind-wandering occurred in men, but not in women, and was accompanied by a change in the content of task-unrelated though, which became more related to other people (as opposed to the self) following tDCS. These findings indicate that mPFC is crucial for mind-wandering, possibly by helping construction of self-relevant scenarios capable to divert attention inward, away from perceptual reality. Gender-related differences in tDCS-induced changes suggest that mPFC controls mind-wandering differently in men and women, which may depend on differences in the structural and functional organization of distributed brain networks governing mind-wandering, including mPFC

Construction of Past and Future Events in Children and Adolescents with ASD: Role of Self-relatedness and Relevance to Decision-Making

We studied episodic memory and future thinking for self-relevant and other-relevant events at different levels of retrieval support, theory of mind, and delay discounting in ASD children and adolescents (ASDs). Compared to typically developing controls, ASDs produced fewer internal (episodic) but a similar number of external (semantic) details while remembering past events, imagining future events, and imagining future events happening to others, indicating a general impairment of event construction. This deficit was driven by group differences under high retrieval support, and therefore unlikely to depend on self-initiated retrieval/construction deficits. ASDs’ event construction impairment related to the severity of ASD symptoms, and to theory of mind deficits. ASDs, however, showed normal delay discounting, highlighting preserved forms of future-based decision-making in ASD

Phase i pharmacokinetic and pharmacodynamic study of lapatinib in combination with sorafenib in patients with advanced refractory solid tumors

Background. The epidermal growth factor receptor (EGFR) and ERBB2 (HER2) pathways and vascular endothelial growth factor (VEGF)-dependent angiogenesis have a pivotal role in cancer pathogenesis and progression. Robust experimental evidence has shown that these pathways are functionally linked and implicated in acquired resistance to targeted therapies making them attractive candidates for joined targeting. We undertook this phase I trial to assess the safety, the recommended dose for phase II trials (RPTD), pharmacokinetics (PK), pharmacodynamics (PD), and the preliminary antitumour activity of the combination of lapatinib and sorafenib in patients with advanced refractory solid tumours. Methods. Four cohorts of at least three patients each received lapatinib once daily and sorafenib twice daily together on a continuous schedule. Doses of lapatinib and sorafenib were escalated based on dose-limiting toxicities (DLTs) in the first treatment cycle following a traditional 3+3 design until the RPTD was reached. Additional patients were treated at the RPTD to characterise PK profiles of this combination and to investigate the potential interaction between lapatinib and sorafenib. Serum samples were collected at baseline and then prospectively every two cycles to assess changes in PD parameters. This trial is registered with ClinicalTrials.gov, number NCT00984425. Findings. Thirty patients with advanced refractory solid tumours were enroled. DLTs were grade three fatigue and grade 3 atypical skin rash observed at dose levels 3 and 4, respectively. The higher dose level explored (lapatinib 1250mg/day and sorafenib 400mg twice daily) represented the RPTD of the combination. The most common drug-related adverse events were fatigue (68%), hypocalcemia (61%), diarrhoea (57%), lymphopaenia (54%), anorexia (50%), rash (50%), and hypophosphatemia (46%). PK analysis revealed no significant effect of sorafenib on the PK profile of lapatinib. Of the 27 assessable patients for clinical activity, one achieved a confirmed complete response, four (15%) had a partial response, and 12 (44%) achieved disease stabilisation. The disease control rate overall was 63%. Interpretation. Combination treatment with lapatinib and sorafenib was feasible with promising clinical activity and without significant PK interactions. Long term tolerability seems to be challenging