Abstract Background In recent years, many studies have evaluated the effects of noninvasive brain stimulation (NIBS) techniques for the treatment of several neurological and psychiatric disorders. ...Positive results led to approval of NIBS for some of these conditions by the Food and Drug Administration in the USA. The therapeutic effects of NIBS have been related to bi-directional changes in cortical excitability with the direction of change depending on the choice of stimulation protocol. Although after-effects are mostly short lived, complex neurobiological mechanisms related to changes in synaptic excitability bear the potential to further induce therapy-relevant lasting changes. Objective To review recent neurobiological findings obtained from in vitro and in vivo studies that highlight molecular and cellular mechanisms of short- and long-term changes of synaptic plasticity after NIBS. Findings Long-term potentiation (LTP) and depression (LTD) phenomena by itself are insufficient in explaining the early and long term changes taking place after short episodes of NIBS. Preliminary experimental studies indicate a complex scenario potentially relevant to the therapeutic effects of NIBS, including gene activation/regulation, de novo protein expression, morphological changes, changes in intrinsic firing properties and modified network properties resulting from changed inhibition, homeostatic processes and glial function. Conclusions This review brings into focus the neurobiological mechanisms underlying long-term after-effects of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) recently obtained from in vitro and in vivo studies, both in animals and humans.
The successful completion of complex tasks like hanging a picture or laparoscopic surgery requires coordinated motion of more than two limbs. User-controlled supernumerary robotic limbs (SL) have ...been proposed to bypass the need for coordination with a partner in such tasks. However, neither the capability to control multiple limbs alone relative to collaborative control with partners, nor how that capability varies across different tasks, is well understood. In this work, we present an investigation of tasks requiring three-hands where the foot was used as an additional source of motor commands. We considered: (1) how does simultaneous control of three hands compare to a cooperating dyad; (2) how this relative performance was altered by the existence of constraints emanating from real or virtual physical connections (mechanical constraints) or from cognitive limits (cognitive constraints). It was found that a cooperating dyad outperformed a single user in all scenarios in terms of task score, path efficiency and motion smoothness. However, while the participants were able to reach more targets with increasing mechanical constraints/decreasing number of simultaneous goals, the relative difference in performance between a dyad and a participant performing trimanual activities decreased, suggesting further potential for SLs in this class of scenario.
Objective: This article presents the development and validation of a new robotic system for Transcranial Magnetic Stimulation (TMS), characterized by a new control approach, and an ad-hoc calibration ...methodology, specifically devised for the TMS application. Methods: The robotic TMS platform is composed of a 7 dof manipulator, controlled by an impedance control, and a camera-based neuronavigation system. The proposed calibration method was optimized on the workspace useful for the specific TMS application (spherical shell around the subject's head), and tested on three different hand-eye and robot-world calibration algorithms. The platform functionality was tested on six healthy subjects during a real TMS procedure, over the left primary motor cortex. Results: employing our method significantly decreases (<inline-formula><tex-math notation="LaTeX">p< 0.001</tex-math></inline-formula>) the calibration error by 34% for the position and 19% for the orientation. The robotic TMS platform achieved greater orientation accuracy than the expert operators, significantly reducing orientation errors by 46% (<inline-formula><tex-math notation="LaTeX">p< 0.001</tex-math></inline-formula>). No significant differences were found in the position errors and in the amplitude of the motor evoked potentials (MEPs) between the robot-aided TMS and the expert operators. Conclusion: The proposed calibration represents a valid method to significantly reduce the calibration errors in robot-aided TMS applications. Results showed the efficacy of the proposed platform (including the control algorithm) in administering a real TMS procedure, achieving better coil positioning than expert operators, and similar results in terms of MEPs. Significance: This article spotlights how to improve the performance of a robotic TMS platform, providing a reproducible and low-cost alternative to the few devices commercially available.
Humans increasingly often act through virtual and robotic avatars, which can feed back to their user only virtual sensory information. Since avatar is user's embodiment and body image is mostly based ...on senses, how virtualization of sensory inputs affects avatar self-attribution is a key question for understanding nowadays human behavior. By manipulating visual and tactile inputs in a series of experiments fashioned after the rubber hand illusion, we assessed the relative weight of the virtualization of sight (Real, Robotic, Virtual) and of touch (Real, Virtual) on artificial hand embodiment. Virtualization decreased embodiment, but unexpectedly lowest embodiment was found when only one sense was virtual. Discordant levels of virtualization of sight and touch elicited revulsion, extending the concept of the uncanny valley to avatar embodiment. Besides timing, spatial constraints and realism of feedback, a matched degree of virtualization of seen and felt stimuli is a further constraint in building the representation of the body.
Breast cancer is a leading malignancy affecting the female population worldwide. Most morbidity is caused by metastases that remain incurable to date. TGF-β1 has been identified as a key driving ...force behind metastatic breast cancer, with promising therapeutic implications.
Employing immunohistochemistry (IHC) analysis, we report, to our knowledge for the first time, that asporin is overexpressed in the stroma of most human breast cancers and is not expressed in normal breast tissue. In vitro, asporin is secreted by breast fibroblasts upon exposure to conditioned medium from some but not all human breast cancer cells. While hormone receptor (HR) positive cells cause strong asporin expression, triple-negative breast cancer (TNBC) cells suppress it. Further, our findings show that soluble IL-1β, secreted by TNBC cells, is responsible for inhibiting asporin in normal and cancer-associated fibroblasts. Using recombinant protein, as well as a synthetic peptide fragment, we demonstrate the ability of asporin to inhibit TGF-β1-mediated SMAD2 phosphorylation, epithelial to mesenchymal transition, and stemness in breast cancer cells. In two in vivo murine models of TNBC, we observed that tumors expressing asporin exhibit significantly reduced growth (2-fold; p = 0.01) and metastatic properties (3-fold; p = 0.045). A retrospective IHC study performed on human breast carcinoma (n = 180) demonstrates that asporin expression is lowest in TNBC and HER2+ tumors, while HR+ tumors have significantly higher asporin expression (4-fold; p = 0.001). Assessment of asporin expression and patient outcome (n = 60; 10-y follow-up) shows that low protein levels in the primary breast lesion significantly delineate patients with bad outcome regardless of the tumor HR status (area under the curve = 0.87; 95% CI 0.78-0.96; p = 0.0001). Survival analysis, based on gene expression (n = 375; 25-y follow-up), confirmed that low asporin levels are associated with a reduced likelihood of survival (hazard ratio = 0.58; 95% CI 0.37-0.91; p = 0.017). Although these data highlight the potential of asporin to serve as a prognostic marker, confirmation of the clinical value would require a prospective study on a much larger patient cohort.
Our data show that asporin is a stroma-derived inhibitor of TGF-β1 and a tumor suppressor in breast cancer. High asporin expression is significantly associated with less aggressive tumors, stratifying patients according to the clinical outcome. Future pre-clinical studies should consider options for increasing asporin expression in TNBC as a promising strategy for targeted therapy.
Highlights • iTBS-induced (intermittent theta burst stimulation) plasticity increases delta EEG. • Delta waves emerge as effectors of cortical plasticity in wakefulness besides sleep. • In patients ...affected by brain lesions, the meaning of slow EEG waves can be reinterpreted.
The development of a new generation of hand prostheses that can ideally approximate the human 'physiological' performance in terms of movement dexterity and sensory feedback for amputees still poses ...many open research challenges. The most promising approaches aim at establishing a direct connection with either the central or the peripheral human nervous system by means of invasive or non-invasive neural interfaces. This paper starts from the assumption that a major contribution to derive functional and technical specifications for such interfaces, and even for the whole prosthetic system, can stem from in-depth analysis of the nervous system reorganization following limb amputation. Neuroplasticity can be modulated by the use of hand prostheses both in the acute phase and in the long-term. We hereby critically review the literature concerning neuroplastic phenomena in amputees, in terms of changes at different CNS levels, particularly for their implications on the development of bidirectional neural interfaces for cybernetic hand prostheses. Our analysis of the literature demonstrates that: (1) the level of CNS reorganization could be used as a parameter of the effectiveness achieved by the prosthetic device and its interfaces, in restoring the hand physiological functionality, (2) the prosthetic system could be seen as a neurorehabilitation tool, as it could induce reduction in aberrant plasticity and promote 'good' plasticity and (3) new generations of 'natural' interfaces can be developed by fully exploiting neuroplastic phenomena to restore neural connections originally governing the lost limb and linking them to the prosthetic system.
Over a lifetime of experience, the representation of the body is built upon congruent integration of multiple elements constituting the sensorimotor loop. To investigate its robustness against the ...rupture of congruency between senses and with motor command, we selectively manipulated in healthy subjects the binds between sight, proprioception, and efferent motor command. Two experiments based on the Moving Hand Illusion were designed employing Tendon Vibration Illusion to modulate proprioception and generate illusory altered feedback of movement. In Experiment A, visuomotor congruency was modulated by introducing adelay between complex multifingered movements performed by arobotic hand and real movement of each participant's hand. In the presence of the motor command, visuomotor congruency enhanced ownership, agency, and skin conductance, while proprioceptive-motor congruency was not effective, confirming the prevalence of vision upon proprioception. In Experiment B, the impact of visuo-proprioceptive congruency was tested in the absence of motor command because the robotic hand moved autonomously. Intersensory congruency compensated for the absence of motor command only for ownership. Skin conductance in Exp Band Proprioceptive Drift in both experiments did not change. Results suggest that ownership and agency are independently processed, and presence of the efferent component modulates sensory feedbacks salience. The brain seems to require the integration of at least two streams of congruent information. Bodily awareness can be generated from sensory information alone, but to feel in charge of the body, senses must be double-checked with the prediction generated from efference copy, which is treated as an additional sensory modality.
The conventional use of prosthetic custom-design socket is affected by discomfort related to wellknown problems: sweating, sores or skin irritation, excessive weight and harness, impaired body image, ...that lead to a high rate of abandonment. Osseointegrated prosthetic implants for limb amputation are progressively evolving to overcome limitations of socket. The aim of this article is to present a systematic review of the use, safety in terms of rate of infection and complications, and reported outcomes of upper and lower limb osseointegrated prosthetic implants. A systematic search was carried out for studies that evaluated outcomes of osseointegration technique in case of upper and lower limb amputees according to the PRISMA guidelines with a PRISMA checklist and algorithm. MINORS score was used for methodologic assessment. 17 articles about the treatment of patients with upper or lower limb amputation treated with an osseointegrated prostesis were included. The overall rate of infections was 32%. All the clinical outcomes reported were related to lower limb. No clinical data for upper limb was found. The postoperative mean value of MCS and PCS SF-36 and Q-TFA was 55.1, 45.4 and 73.8 respectively, while six minute walk test (6MWT) and the timed up and go (TUG) test scored an average value of 388 meters and 11.5 seconds respectively. MINORS score ranged from 5 to 13, with a median of 11 interquartile range (IQR), 9-11. The osseointegration is associated to a high rate of postoperative complications but, significant improvement in clinical outcomes compared to preoperative time are shown. The data available from the literature are limited but suggest good clinical outcomes and significant survivorship of the implants. Further clinical studies are needed to establish which kind of implant is associated to higher clinical performance and lower rate of postoperative complications and infections.
Although real-time 3D echocardiography (RT3DE) has only been introduced in the last decades, its use still needs to be improved since it is a time-consuming and operator-dependent technique and ...acquiring a good quality data can be difficult. Moreover, the additive value of this important diagnostic tool still needs to be wholly appreciated in clinical practice. This review aims at explaining how, why, and when performing RT3DE is useful in clinical practice.
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