Integration of proprioception in upper limb prostheses through non-invasive strategies: a review.

Proprioception plays a key role in moving our body dexterously and effortlessly. Nevertheless, the majority of investigations evaluating the benefits of providing supplemental feedback to prosthetics users focus on delivering touch restitution. These studies evaluate the influence of touch sensation in an attempt to improve the controllability of current robotic devices. Contrarily, investigations evaluating the capabilities of proprioceptive supplemental feedback have yet to be comprehensively analyzed to the same extent, marking a major gap in knowledge within the current research climate. The non-invasive strategies employed so far to restitute proprioception are reviewed in this work. In the absence of a clearly superior strategy, approaches employing vibrotactile, electrotactile and skin-stretch stimulation achieved better and more consistent results, considering both kinesthetic and grip force information, compared with other strategies or any incidental feedback. Although emulating the richness of the physiological sensory return through artificial feedback is the primary hurdle, measuring its effects to eventually support the integration of cumbersome and energy intensive hardware into commercial prosthetic devices could represent an even greater challenge. Thus, we analyze the strengths and limitations of previous studies and discuss the possible benefits of coupling objective measures, like neurophysiological parameters, as well as measures of prosthesis embodiment and cognitive load with behavioral measures of performance. Such insights aim to provide additional and collateral outcomes to be considered in the experimental design of future investigations of proprioception restitution that could, in the end, allow researchers to gain a more detailed understanding of possibly similar behavioral results and, thus, support one strategy over another.

Sensorimotor integration within the primary motor cortex by selective nerve fascicle stimulation.

The integration of sensory inputs in the motor cortex is crucial for dexterous movement. We recently demonstrated that a closed-loop control based on the feedback provided through intraneural multichannel electrodes implanted in the median and ulnar nerves of a participant with upper limb amputation improved manipulation skills and increased prosthesis embodiment. Here we assessed, in the same participant, whether and how selective intraneural sensory stimulation also elicits a measurable cortical activation and affects sensorimotor cortical circuits. After estimating the activation of the primary somatosensory cortex evoked by intraneural stimulation, sensorimotor integration was investigated by testing the inhibition of primary motor cortex (M1) output to transcranial magnetic stimulation, after both intraneural and perineural stimulation. Selective sensory intraneural stimulation evoked a low-amplitude, 16 ms-latency, parietal response in the same area of the earliest component evoked by whole-nerve stimulation, compatible with fast-conducting afferent fibre activation. For the first time, we show that the same intraneural stimulation was also capable of decreasing M1 output, at the same time range of the short-latency afferent inhibition effect of whole-nerve superficial stimulation. The inhibition generated by the stimulation of channels activating only sensory fibres was stronger than that due to intraneural or perineural stimulation of channels activating mixed fibres. We demonstrate in a human subject that the cortical sensorimotor integration inhibiting M1 output previously described after the experimental whole-nerve stimulation is present also with a more ecological selective sensory fibre stimulation. KEY POINTS: Cortical integration of sensory inputs is crucial for dexterous movement. Short-latency somatosensory afferent inhibition of motor cortical output is typically produced by peripheral whole-nerve stimulation. We exploited intraneural multichannel electrodes used to provide sensory feedback for prosthesis control to assess whether and how selective intraneural sensory stimulation affects sensorimotor cortical circuits in humans. Activation of the primary somatosensory cortex (S1) was explored by recording scalp somatosensory evoked potentials. Sensorimotor integration was tested by measuring the inhibitory effect of the afferent stimulation on the output of the primary motor cortex (M1) generated by transcranial magnetic stimulation. We demonstrate in humans that selective intraneural sensory stimulation elicits a measurable activation of S1 and that it inhibits the output of M1 at the same time range of whole-nerve superficial stimulation.

Resting state network connectivity is attenuated by fMRI acoustic noise.

INTRODUCTION: During the past decades there has been an increasing interest in tracking brain network fluctuations in health and disease by means of resting state functional magnetic resonance imaging (rs-fMRI). Rs-fMRI however does not provide the ideal environmental setting, as participants are continuously exposed to noise generated by MRI coils during acquisition of Echo Planar Imaging (EPI). We investigated the effect of EPI noise on resting state activity and connectivity using magnetoencephalography (MEG), by reproducing the acoustic characteristics of rs-fMRI environment during the recordings. As compared to fMRI, MEG has little sensitivity to brain activity generated in deep brain structures, but has the advantage to capture both the dynamic of cortical magnetic oscillations with high temporal resolution and the slow magnetic fluctuations highly correlated with BOLD signal. METHODS: Thirty healthy subjects were enrolled in a counterbalanced design study including three conditions: a) silent resting state (Silence), b) resting state upon EPI noise (fMRI), and c) resting state upon white noise (White). White noise was employed to test the specificity of fMRI noise effect. The amplitude envelope correlation (AEC) in alpha band measured the connectivity of seven Resting State Networks (RSN) of interest (default mode network, dorsal attention network, language, left and right auditory and left and right sensory-motor). Vigilance dynamic was estimated from power spectral activity. RESULTS: fMRI and White acoustic noise consistently reduced connectivity of cortical networks. The effects were widespread, but noise and network specificities were also present. For fMRI noise, decreased connectivity was found in the right auditory and sensory-motor networks. Progressive increase of slow theta-delta activity related to drowsiness was found in all conditions, but was significantly higher for fMRI . Theta-delta significantly and positively correlated with variations of cortical connectivity. DISCUSSION: rs-fMRI connectivity is biased by unavoidable environmental factors during scanning, which warrant more careful control and improved experimental designs. MEG is free from acoustic noise and allows a sensitive estimation of resting state connectivity in cortical areas. Although underutilized, MEG could overcome issues related to noise during fMRI, in particular when investigation of motor and auditory networks is needed.

BDNF polymorphism and interhemispheric balance of motor cortex excitability: a preliminary study.

Preclinical studies have demonstrated that brain-derived neurotrophic factor (BDNF) plays a crucial role in the homeostatic regulation of cortical excitability and excitation/inhibition balance. Using transcranial magnetic stimulation techniques, we investigated whether BDNF polymorphism could influence cortical excitability of the left and right primary motor cortex in healthy humans. Twenty-nine participants were recruited and genotyped for the presence of the BDNF Val66Met polymorphism, namely homozygous for the valine allele (Val/Val), heterozygotes (Val/Met), and homozygous for the methionine allele (Met/Met). Blinded to the latter, we evaluated inhibitory and facilitatory circuits of the left (LH) and right motor cortex (RH) by measuring resting (RMT) and active motor threshold (AMT), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). For each neurophysiological metric, we also considered the interhemispheric balance expressed by the laterality index (LI). Val/Val participants (n = 21) exhibited an overall higher excitability of the LH compared with the RH, as probed by lower motor thresholds, lower SICI, and higher ICF. Val/Val participants displayed positive LI, especially for AMT and ICF (all P < 0.05), indicating higher LH excitability and more pronounced interhemispheric excitability imbalance as compared with Met carriers. Our preliminary results suggest that BDNF Val66Met polymorphism might influence interhemispheric balance of motor cortex excitability.NEW & NOTEWORTHY BDNF Val66Met polymorphism might influence interhemispheric balance of motor cortex excitability. Specifically, Val/Val carriers display higher excitability of the left compared with the right primary motor cortex, whereas Met carriers do not show any significant corticomotor excitability imbalance. These preliminary results are relevant to understanding aberrant interhemispheric excitability and excitation/inhibition balance in neurological disorders.

Behavioral and Physiological Evidence of a favored Hand Posture in the Body Representation for Action.

Motor planning and execution require a representational map of our body. Since the body can assume different postures, it is not known how it is represented in this map. Moreover, is the generation of the motor command favored by some body configurations? We investigated the existence of a centrally favored posture of the hand for action, in search of physiological and behavioral advantages due to central motor processing. We tested two opposite hand pinch grips, equally difficult and commonly used: forearm pronated, thumb-down, index-up pinch against the same grip performed with thumb-up. The former revealed faster movement onset, sign of faster neural computation, and faster target reaching. It induced increased corticospinal excitability, independently on pre-stimulus tonic muscle contraction. Remarkably, motor excitability also increased when thumb-down pinch was only observed, imagined, or prepared, actually keeping the hand at rest. Motor advantages were independent of any concurrent modulation due to somatosensory input, as shown by testing afferent inhibition. Results provide strong behavioral and physiological evidence for a preferred hand posture favoring brain motor control, independently by somatosensory processing. This suggests the existence of a baseline postural representation that may serve as an a priori spatial reference for body-space interaction.

Design of multi-pad electrotactile system envisioned as a feedback channel for supernumerary robotic limbs.

BACKGROUND: Providing real-time haptic feedback is an important, but still not sufficiently explored aspect of the use of supernumerary robotic limbs (SRLs). We present a multi-pad electrode for conveying multi-modal proprioceptive and sensory information from SRL to the user's thigh and propose a method for stimuli calibration. METHODS: Within two pilot tests, we investigated return electrode configuration and active electrode discrimination in three healthy subjects to select the appropriate electrode pad topology. Based on the obtained results and anthropometric data from the literature, the electrode was designed to have three branches of 10 pads and two additional pads that can be displaced over/under the electrode branches. The electrode was designed to be connected to the stimulator that allows full multiplexing so that specific branches can serve as a common return electrode. To define the procedure for application of this system, the sensation, localization, and discomfort thresholds applicable for the novel electrode were determined and analyzed in 10 subjects. RESULTS: The results showed no overlaps between the three thresholds for individual pads, with significantly different average values, suggesting that the selected electrode positioning and design provide a good active range of useful current amplitude. The results of the subsequent analysis suggested that the stimuli intensity level of 200% of the sensation threshold is the most probable value of the localization threshold. Furthermore, this level ensures a low chance (i.e., 0.7%) of reaching the discomfort. CONCLUSIONS: We believe that envisioned electrotactile system could serve as a high bandwidth feedback channel that can be easily set up to provide proprioceptive and sensory feedback from supernumerary limbs.

A Soft Zwitterionic Hydrogel as Potential Coating on a Polyimide Surface to Reduce Foreign Body Reaction to Intraneural Electrodes.

Invasive intraneural electrodes can control advanced neural-interfaced prostheses in human amputees. Nevertheless, in chronic implants, the progressive formation of a fibrotic capsule can gradually isolate the electrode surface from the surrounding tissue leading to loss of functionality. This is due to a nonspecific inflammatory response called foreign-body reaction (FBR). The commonly used poly(ethylene glycol) (PEG)-based low-fouling coatings of implantable devices can be easily encapsulated and are susceptible to oxidative damage in long-term in vivo applications. Recently, sulfobetaine-based zwitterionic hydrogels have emerged as an important class of robust ultra-low fouling biomaterials, holding great potential to mitigate FBR. The aim of this proof-of-principle in vitro work was to assess whether the organic zwitterionic-poly(sulfobetaine methacrylate) [poly(SBMA)]-hydrogel could be a suitable coating for Polyimide (PI)-based intraneural electrodes to reduce FBR. We first synthesized and analyzed the hydrogel through a mechanical characterization (i.e., Young's modulus). Then, we demonstrated reduced adhesion and activation of fibrogenic and pro-inflammatory cells (i.e., human myofibroblasts and macrophages) on the hydrogel compared with PEG-coated and polystyrene surfaces using cell viability assays, confocal fluorescence microscopy and high-content analysis of oxidative stress production. Interestingly, we successfully coated PI surfaces with a thin film of the hydrogel through covalent bond and demonstrated its high hydrophilicity via water contact angle measurement. Importantly, we showed the long-term release of an anti-fibrotic drug (i.e., Everolimus) from the hydrogel. Because of the low stiffness, biocompatibility, high hydration and ultra-low fouling characteristics, our zwitterionic hydrogel could be envisioned as long-term diffusion-based delivery system for slow and controlled anti-inflammatory and anti-fibrotic drug release in vivo.

Neurophysiology of slip sensation and grip reaction: insights for hand prosthesis control of slippage.

Sensory feedback is pivotal for a proficient dexterity of the hand. By modulating the grip force in function of the quick and not completely predictable change of the load force, grabbed objects are prevented to slip from the hand. Slippage control is an enabling achievement to all manipulation abilities. However, in hand prosthetics, the performance of even the most innovative research solutions proposed so far to control slippage remain distant from the human physiology. Indeed, slippage control involves parallel and compensatory activation of multiple mechanoceptors, spinal and supraspinal reflexes, and higher-order voluntary behavioral adjustments. In this work, we reviewed the literature on physiological correlates of slippage to propose a three-phases model for the slip sensation and reaction. Furthermore, we discuss the main strategies employed so far in the research studies that tried to restore slippage control in amputees. In the light of the proposed three-phase slippage model and from the weaknesses of already implemented solutions, we proposed several physiology-inspired solutions for slippage control to be implemented in the future hand prostheses. Understanding the physiological basis of slip detection and perception and implementing them in novel hand feedback system would make prosthesis manipulation more efficient and would boost its perceived naturalness, fostering the sense of agency for the hand movements.

Does sonification of action simulation training impact corticospinal excitability and audiomotor plasticity?

Sonification is a sensory augmentation strategy whereby a sound is associated with, and modulated by, movement. Evidence suggests that sonification could be a viable strategy to maximize learning and rehabilitation. Recent studies investigated sonification of action observation, reporting beneficial effects, especially in Parkinson's disease. However, research on simulation training-a training regime based on action observation and motor imagery, in which actions are internally simulated, without physical execution-suggest that action observation alone is suboptimal, compared to the combined use of action observation and motor imagery. In this study, we explored the effects of sonified action observation and motor imagery on corticospinal excitability, as well as to evaluate the extent of practice-dependent plasticity induced by this training. Nineteen participants were recruited to complete a practice session based on combined and congruent action observation and motor imagery (AOMI) and physical imitation of the same action. Prior to the beginning, participants were randomly assigned to one of two groups, one group (nine participants) completed the practice block with sonified AOMI, while the other group (ten participants) completed the practice without extrinsic auditory information and served as control group. To investigate practice-induced plasticity, participants completed two auditory paired associative stimulation (aPAS) protocols, one completed after the practice block, and another one completed alone, without additional interventions, at least 7 days before the practice. After the practice block, both groups significantly increased their corticospinal excitability, but sonification did not exert additional benefits, compared to non-sonified conditions. In addition, aPAS significantly increased corticospinal excitability when completed alone, but when it was primed by a practice block, no modulatory effects on corticospinal excitability were found. It is possible that sonification of combined action observation and motor imagery may not be a useful strategy to improve corticospinal, but further studies are needed to explore its relationship with performance improvements. We also confirm the neuromodulatory effect of aPAS, but its interaction with audiomotor practice remain unclear.

Sonification of combined action observation and motor imagery: Effects on corticospinal excitability.

Action observation and motor imagery are valuable strategies for motor learning. Their simultaneous use (AOMI) increases neural activity, with related benefits for motor learning, compared to the two strategies alone. In this study, we explored how sonification influences AOMI. Twenty-five participants completed a practice block based on AOMI, motor imagery and physical execution of the same action. Participants were divided into two groups: An experimental group that practiced with sonification during AOMI (sAOMI), and a control group, which did not receive any extrinsic feedback. Corticospinal excitability at rest and during action observation and AOMI was assessed before and after practice, with and without sonification sound, to test the development of an audiomotor association. The practice block increased corticospinal excitability in all testing conditions, but sonification did not affect this. In addition, we found no differences in action observation and AOMI, irrespective of sonification. These results suggest that, at least for simple tasks, sonification of AOMI does not influence corticospinal excitability; In these conditions, sonification may have acted as a distractor. Future studies should further explore the relationship between task complexity, value of auditory information and action, to establish whether sAOMI is a valuable for motor learning.

Modulation of Body Representation Impacts on Efferent Autonomic Activity.

The afferent branch of the autonomic nervous system contributes with interoception to the multimodal sensory correlation continuously needed to update our representation of the body. To test whether the modulation of body representation would have an impact on the efferent branch of the autonomic nervous system, nonspecific skin conductance has been measured in three rubber hand illusion (RHI) experiments, controlled with asynchronous brush-stroking and incongruent fake hand position. Nonspecific skin conductance standard deviation (SCSD) computed along the whole 90 sec of stroking was found to be increased by the illusion and to correlate with all the typical measures of embodiment. Computing SCSD in shorter time windows strongly enhanced the difference between illusion and controls. The highest difference was found in the 10-55 sec window, being the 14-34 sec window as the most informative one. The higher correlations with the validated measures of embodiment (all but the proprioceptive drift) were found for time windows ranging between 35 and 65 sec. The SCSD was no longer significantly higher when the RHI was repeated twice (two trials each iteration), but it was still significantly higher in synchronous stroking even when considering only the second trial. However, after the first iteration of the RHI paradigm, the effect of the embodiment on nonspecific skin conductance response results to be attenuated, suggesting that novelty in presentation of the RHI can contribute to the effect on nonspecific skin conductance response. Results candidate SCSD as a noninvasive, cheap, easy, and objective measure of embodiment, especially sensible to onset and strength of the illusion. Alike the already known enhanced autonomic reaction to a threatening, SCSD does not interfere with the collection of other behavioral measures. Correlations and their dynamics, presence of the effect in the second presentation of the setup but relative low robustness against multiple repetition, suggest that the increased fluctuations of skin conductance caught by SCSD are not just the effect of different presented sensory stimuli but more likely a stronger arousal response to the novelty of the updated perceptual status.

Embodying melody through a conducting baton: a pilot comparison between musicians and non-musicians.

Finger-tapping tasks have been widely adopted to investigate auditory-motor synchronization, i.e., the coupling of movement with an external auditory rhythm. However, the discrete nature of these movements usually limits their application to the study of beat perception in the context of isochronous rhythms. The purpose of the present pilot study was to test an innovative task that allows investigating bodily responses to complex, non-isochronous rhythms. A conductor's baton was provided to 16 healthy subjects, divided into 2 different groups depending on the years of musical training they had received (musicians or non-musicians). Ad hoc-created melodies, including notes of different durations, were played to the subjects. Each subject was asked to move the baton up and down according to the changes in pitch contour. Software for video analysis and modelling (Tracker®) was used to track the movement of the baton tip. The main parameters used for the analysis were the velocity peaks in the vertical axis. In the musician group, the number of velocity peaks exactly matched the number of notes, while in the non-musician group, the number of velocity peaks exceeded the number of notes. An exploratory data analysis using Poincaré plots suggested a greater degree of coupling between hand-arm movements and melody in musicians both with isochronous and non-isochronous rhythms. The calculated root mean square error (RMSE) between the note onset times and the velocity peaks, and the analysis of the distribution of velocity peaks in relationship to note onset times confirmed the effect of musical training. Notwithstanding the small number of participants, these results suggest that this novel behavioural task could be used to investigate auditory-motor coupling in the context of music in an ecologically valid setting. Furthermore, the task may be used for rhythm training and rehabilitation in neurological patients with movement disorders.

Evaluation and Treatment of Vascular Cognitive Impairment by Transcranial Magnetic Stimulation.

The exact relationship between cognitive functioning, cortical excitability, and synaptic plasticity in dementia is not completely understood. Vascular cognitive impairment (VCI) is deemed to be the most common cognitive disorder in the elderly since it encompasses any degree of vascular-based cognitive decline. In different cognitive disorders, including VCI, transcranial magnetic stimulation (TMS) can be exploited as a noninvasive tool able to evaluate in vivo the cortical excitability, the propension to undergo neural plastic phenomena, and the underlying transmission pathways. Overall, TMS in VCI revealed enhanced cortical excitability and synaptic plasticity that seem to correlate with the disease process and progression. In some patients, such plasticity may be considered as an adaptive response to disease progression, thus allowing the preservation of motor programming and execution. Recent findings also point out the possibility to employ TMS to predict cognitive deterioration in the so-called "brains at risk" for dementia, which may be those patients who benefit more of disease-modifying drugs and rehabilitative or neuromodulatory approaches, such as those based on repetitive TMS (rTMS). Finally, TMS can be exploited to select the responders to specific drugs in the attempt to maximize the response and to restore maladaptive plasticity. While no single TMS index owns enough specificity, a panel of TMS-derived measures can support VCI diagnosis and identify early markers of progression into dementia. This work reviews all TMS and rTMS studies on VCI. The aim is to evaluate how cortical excitability, plasticity, and connectivity interact in the pathophysiology of the impairment and to provide a translational perspective towards novel treatments of these patients. Current pitfalls and limitations of both studies and techniques are also discussed, together with possible solutions and future research agenda.

Transcranial direct current stimulation over the sensory-motor regions inhibits gamma synchrony.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique able to induce plasticity phenomena. Although tDCS application has been spreading over a variety of neuroscience domains, the mechanisms by which the stimulation acts are largely unknown. We investigated tDCS effects on cortical gamma synchrony, which is a crucial player in cortical function. We performed a randomized, sham-controlled, double-blind study on healthy subjects, combining tDCS and magnetoencephalography. By driving brain activity via 40 Hz auditory stimulation during magnetoencephalography, we experimentally tuned cortical gamma synchrony and measured it before and after bilateral tDCS of the primary sensory-motor hand regions (anode left, cathode right). We demonstrated that the stimulation induces a remarkable decrease of gamma synchrony (13 out of 15 subjects), as measured by gamma phase at 40 Hz. tDCS has strong remote effects, as the cortical region mostly affected was located far away from the stimulation site and covered a large area of the right centro-temporal cortex. No significant differences between stimulations were found for baseline gamma synchrony, as well as early transient auditory responses. This suggests a specific tDCS effect on externally driven gamma synchronization. This study sheds new light on the effect of tDCS on cortical function showing that the net effect of the stimulation on cortical gamma synchronization is an inhibition.

Bilateral Transcranial Direct Current Stimulation Reshapes Resting-State Brain Networks: A Magnetoencephalography Assessment.

Transcranial direct current stimulation (tDCS) can noninvasively induce brain plasticity, and it is potentially useful to treat patients affected by neurological conditions. However, little is known about tDCS effects on resting-state brain networks, which are largely involved in brain physiological functions and in diseases. In this randomized, sham-controlled, double-blind study on healthy subjects, we have assessed the effect of bilateral tDCS applied over the sensorimotor cortices on brain and network activity using a whole-head magnetoencephalography system. Bilateral tDCS, with the cathode (-) centered over C4 and the anode (+) centered over C3, reshapes brain networks in a nonfocal fashion. Compared to sham stimulation, tDCS reduces left frontal alpha, beta, and gamma power and increases global connectivity, especially in delta, alpha, beta, and gamma frequencies. The increase of connectivity is consistent across bands and widespread. These results shed new light on the effects of tDCS and may be of help in personalizing treatments in neurological disorders.

A novel c132-134del mutation in Unverricht-Lundborg disease and the review of literature of heterozygous compound patients.

Unverricht-Lundborg disease or progressive myoclonic epilepsy type 1 (EPM1) is an autosomal recessive disease caused by mutation of the cystatin B gene (CSTB), located on chromosome 21q22.3. The most common mutation is an expansion of unstable dodecamer repetition (CCCCGCCCCGCG), whereas other types of mutations are rare. Among these, heterozygous compound mutations are described to induce a more severe phenotype than that of homozygous dodecameric repetition. We report two siblings affected by heterozygous compound mutations carrying a novel mutation of the deletion of three nucleotides in exon 2 of the gene in position 132-134 of the coding sequence (c.132-134del) in the allele not including the dodecamer repetition. This mutation results in the loss of two amino acid residues and insertion of an asparagine in position 44 (p.Lys44_Ser45delinsAsn). Our patients presented a very different clinical picture. The male patient had a severe myoclonus, drug-resistant epilepsy and psychiatric comorbidity, while his affected sister had only very rare seizures and sporadic myoclonic jerks at awakening. The revision of literature about heterozygous compound EPM1 patients confirms this gender phenotypic expressivity, with female patients carrying less severe symptoms than male patients. These data lead to the hypothesis of complex gender-specific factors interacting with CSTB expressivity in EPM1 patients.

Linking cognitive abilities with the propensity for risk-taking: the balloon analogue risk task.

There is great interest about the individual differences that influence the ability of dealing with risky decisions. In this light, an intriguing question is whether decision-making during risk is related to other cognitive abilities, especially executive functions. To investigate, in healthy subjects, the existence of a possible correlation between risk-taking and cognitive abilities, the balloon analogue risk task (BART) has been exploited to assess risk-taking propensity and the random number generation (RNG), to investigate cognitive functions. The risk-taking propensity is significantly correlated with the Cycling factor, a feature of RNG performance specifically related to the ability of updating and monitoring information. In particular, an excessive activity of monitoring (expressed by lower values of Cycling factor) is related to a more risk-averse behavior. An overlapping between the circuits involved in both RNG and BART, centered on the dorsolateral prefrontal cortex, could be the possible neurophysiological substrate for this correlation. This study suggests a relevant contribution of executive functions in risk-taking behavior. This could have relevant implications in neuroeconomics and neuropsychiatry of addiction and pathological gambling.

The effect of transcutaneous vagus nerve stimulation on cortical excitability.

There is great interest about the therapeutic potentialities of transcutaneous vagus nerve stimulation (tVNS) applied to neuropsychiatric disorders. However, the mechanisms of action of tVNS and its impact on cortical excitability are unclear. To this regard, transcranial magnetic stimulation (TMS) can be useful because it is able of evaluating non-invasively excitatory and inhibitory circuitry of the human cortex. Aim of the present study is to investigate the effects of tVNS on cerebral cortex excitability in healthy volunteers by means of TMS. Ten healthy subjects participated in this randomized placebo-controlled double-blind study. Real tVNS was administered at left external acoustic meatus, while sham stimulation was performed at left ear lobe, both of them for 60 min. We evaluated motor thresholds, motor evoked potential amplitude, recruitment curves, and short-interval intracortical inhibition (SICI) in right and left motor cortex. Such parameters were evaluated before and 60 min after the exposure to tVNS, for both the real and the sham stimulation. Cardiovascular parameters were monitored during the stimulation. A generalized linear model for repeated measures was implemented to assess the effect of time and stimulation type on cardiovascular and neurophysiological variables. SICI, a double-pulse TMS paradigm informative of GABA-A activity, was significantly increased in right motor cortex after real tVNS. Other neurophysiological parameters, as well as cardiovascular variables, remained unchanged. Our findings confirm that tVNS is a safe and effective way to stimulate vagus nerve and provide innovative data about the possible mechanisms of action that supports the potential therapeutic application of this technique.

The effect of practice on random number generation task: a transcranial direct current stimulation study.

Random number generation (RNG) is a procedurally-simple task related to specific executive functions, such as updating and monitoring of information and inhibition of automatic responses. The effect of practice on executive functions has been widely investigated, however little is known on the impact of practice on RNG. Transcranial direct current stimulation (tDCS) allows to modulate, non-invasively, brain activity and to enhance the effects of training on executive functions. Hence, this study aims to investigate the effect of practice on RNG and to explore the possibility to influence it by tDCS applied over dorsolateral prefrontal cortex. Twenty-six healthy volunteers have been evaluated within single session and between different sessions of RNG using several measures of randomness, which are informative of separable cognitive components servicing random behavior. We found that repetition measures significantly change within single session, seriation measures significantly change both within and between sessions, while cycling measures are not affected by practice. tDCS does not produce any additional effect, however a sub-analysis limited to the first session revealed an increasing trend in seriation measure after anodal compared to cathodal stimulation. Our findings support the hypothesis that practice selectively and consistently influences specific cognitive components related to random behavior, while tDCS transiently affects RNG performance.