The consequences of the new European reclassification of non-invasive brain stimulation devices and the medical device regulations pose an existential threat to research and treatment: An invited opinion paper.

A significant amount of European basic and clinical neuroscience research includes the use of transcranial magnetic stimulation (TMS) and low intensity transcranial electrical stimulation (tES), mainly transcranial direct current stimulation (tDCS). Two recent changes in the EU regulations, the introduction of the Medical Device Regulation (MDR) (2017/745) and the Annex XVI have caused significant problems and confusions in the brain stimulation field. The negative consequences of the MDR for non-invasive brain stimulation (NIBS) have been largely overlooked and until today, have not been consequently addressed by National Competent Authorities, local ethical committees, politicians and by the scientific communities. In addition, a rushed bureaucratic decision led to seemingly wrong classification of NIBS products without an intended medical purpose into the same risk group III as invasive stimulators. Overregulation is detrimental for any research and for future developments, therefore researchers, clinicians, industry, patient representatives and an ethicist were invited to contribute to this document with the aim of starting a constructive dialogue and enacting positive changes in the regulatory environment.

Minimal detectable change of gait and balance measures in older neurological patients: estimating the standard error of the measurement from before-after rehabilitation data thanks to the linear mixed-effects models.

BACKGROUND: Tracking gait and balance impairment in time is paramount in the care of older neurological patients. The Minimal Detectable Change (MDC), built upon the Standard Error of the Measurement (SEM), is the smallest modification of a measure exceeding the measurement error. Here, a novel method based on linear mixed-effects models (LMMs) is applied to estimate the standard error of the measurement from data collected before and after rehabilitation and calculate the MDC of gait and balance measures. METHODS: One hundred nine older adults with a gait impairment due to neurological disease (66 stroke patients) completed two assessment sessions before and after inpatient rehabilitation. In each session, two trials of the 10-meter walking test and the Timed Up and Go (TUG) test, instrumented with inertial sensors, have been collected. The 95% MDC was calculated for the gait speed, TUG test duration (TTD) and other measures from the TUG test, including the angular velocity peak (ωpeak) in the TUG test's turning phase. Random intercepts and slopes LMMs with sessions as fixed effects were used to estimate SEM. LMMs assumptions (residuals normality and homoscedasticity) were checked, and the predictor variable ln-transformed if needed. RESULTS: The MDC of gait speed was 0.13 m/s. The TTD MDC, ln-transformed and then expressed as a percentage of the baseline value to meet LMMs' assumptions, was 15%, i.e. TTD should be < 85% of the baseline value to conclude the patient's improvement. ωpeak MDC, also ln-transformed and expressed as the baseline percentage change, was 25%. CONCLUSIONS: LMMs allowed calculating the MDC of gait and balance measures even if the test-retest steady-state assumption did not hold. The MDC of gait speed, TTD and ωpeak from the TUG test with an inertial sensor have been provided. These indices allow monitoring of the gait and balance impairment, which is central for patients with an increased falling risk, such as neurological old persons. TRIAL REGISTRATION: NA.

The sense of agency in near and far space.

The sense of agency is the ability to recognize that we are the actors of our actions and their consequences. We explored whether and how spatial cues may modulate the agency experience by manipulating the ecological validity of the experimental setup (real-space or computer-based setup) and the distance of the action-outcome (near or far). We tested 58 healthy adults collecting explicit agency judgments and the perceived time interval between movements and outcomes (to quantify the intentional binding phenomenon, an implicit index of agency). Participants show greater implicit agency for voluntary actions when there is a temporal and spatial action-outcome contingency. Conversely, participants reported similar explicit agency for outcomes appearing in the near and far space. Notably, these effects were independent of the ecological validity of the setting. These results suggest that spatial proximity, realistic or illusory, is essential for feeling implicitly responsible for the consequences of our actions.

The effects of occipital and parietal tDCS on chronic visual field defects after brain injury.

Introduction: Homonymous visual field defects (HVFDs) following acquired brain lesions affect independent living by hampering several activities of everyday life. Available treatments are intensive and week- or month-long. Transcranial Direct current stimulation (tDCS), a plasticity-modulating non-invasive brain stimulation technique, could be combined with behavioral trainings to boost their efficacy or reduce treatment duration. Some promising attempts have been made pairing occipital tDCS with visual restitution training, however less is knows about which area/network should be best stimulated in association with compensatory approaches, aimed at improving exploratory abilities, such as multisensory trainings. Methods: In a proof-of-principle, sham-controlled, single-blind study, 15 participants with chronic HVFDs underwent four one-shot sessions of active or sham anodal tDCS applied over the ipsilesional occipital cortex, the ipsilesional or contralesional posterior parietal cortex. tDCS was delivered during a compensatory multisensory (audiovisual) training. Before and immediately after each tDCS session, participants carried out a visual detection task, and two visual search tasks (EF and Triangles search tests). Accuracy (ACC) and response times (RTs) were analyzed with generalized mixed models. We investigated differences in baseline performance, clinical-demographic and lesion factors between tDCS responders and non-responders, based on post-tDCS behavioral improvements. Lastly, we conducted exploratory analyses to compare left and right brain-damaged participants. Results: RTs improved after active ipsilesional occipital and parietal tDCS in the visual search tasks, while no changes in ACC were detected. Responders to ipsilesional occipital tDCS (Triangle task) had shorter disease duration and smaller lesions of the parietal cortex and the superior longitudinal fasciculus. On the other end, on the EF test, those participants with larger damage of the temporo-parietal cortex or the fronto-occipital white matter tracts showed a larger benefit from contralesional parietal tDCS. Overall, the visual search RTs improvements were larger in participants with right-sided hemispheric lesions. Conclusion: The present result shows the facilitatory effects of occipital and parietal tDCS combined with compensatory multisensory training on visual field exploration in HVFDs, suggesting a potential for the development of new neuromodulation treatments to improve visual scanning behavior in brain-injured patients.

The emergence of the multisensory brain: From the womb to the first steps.

The becoming of the human being is a multisensory process that starts in the womb. By integrating spontaneous neuronal activity with inputs from the external world, the developing brain learns to make sense of itself through multiple sensory experiences. Over the past ten years, advances in neuroimaging and electrophysiological techniques have allowed the exploration of the neural correlates of multisensory processing in the newborn and infant brain, thus adding an important piece of information to behavioral evidence of early sensitivity to multisensory events. Here, we review recent behavioral and neuroimaging findings to document the origins and early development of multisensory processing, particularly showing that the human brain appears naturally tuned to multisensory events at birth, which requires multisensory experience to fully mature. We conclude the review by highlighting the potential uses and benefits of multisensory interventions in promoting healthy development by discussing emerging studies in preterm infants.

The Telephone Language Screener (TLS): standardization of a novel telephone-based screening test for language impairment.

BACKGROUND: This study aimed at developing and standardizing the Telephone Language Screener (TLS), a novel, disease-nonspecific, telephone-based screening test for language disorders. METHODS: The TLS was developed in strict pursuance to the current psycholinguistic standards. It comprises nine tasks assessing phonological, lexical-semantic and morpho-syntactic components, as well as an extra Backward Digit Span task. The TLS was administered to 480 healthy participants (HPs), along with the Telephone-based Semantic Verbal Fluency (t-SVF) test and a Telephone-based Composite Language Index (TBCLI), as well as to 37 cerebrovascular/neurodegenerative patients-who also underwent the language subscale of the Telephone Interview for Cognitive Status (TICS-L). An HP subsample was also administered an in-person language battery. Construct validity, factorial structure, internal consistency, test-retest and inter-rater reliability were tested. Norms were derived via Equivalent Scores. The capability of the TLS to discriminate patients from HPs and to identify, among the patient cohort, those with a defective TICS-L, was also examined. RESULTS: The TLS was underpinned by a mono-component structure and converged with the t-SVF (p < .001), the TBCLI (p < .001) and the in-person language battery (p = .002). It was internally consistent (McDonald's ω = 0.67) and reliable between raters (ICC = 0.99) and at retest (ICC = 0.83). Age and education, but not sex, were predictors of TLS scores. The TLS optimally discriminated patients from HPs (AUC = 0.80) and successfully identified patients with an impaired TICS-L (AUC = 0.92). In patients, the TLS converged with TICS-L scores (p = 0.016). DISCUSSION: The TLS is a valid, reliable, normed and clinically feasible telephone-based screener for language impairment.

Seeing emotions in the eyes: a validated test to study individual differences in the perception of basic emotions.

People are able to perceive emotions in the eyes of others and can therefore see emotions when individuals wear face masks. Research has been hampered by the lack of a good test to measure basic emotions in the eyes. In two studies respectively with 358 and 200 participants, we developed a test to see anger, disgust, fear, happiness, sadness and surprise in images of eyes. Each emotion is measured with 8 stimuli (4 male actors and 4 female actors), matched in terms of difficulty and item discrimination. Participants reliably differed in their performance on the Seeing Emotions in the Eyes test (SEE-48). The test correlated well not only with Reading the Mind in the Eyes Test (RMET) but also with the Situational Test of Emotion Understanding (STEU), indicating that the SEE-48 not only measures low-level perceptual skills but also broader skills of emotion perception and emotional intelligence. The test is freely available for research and clinical purposes.

Neuromodulation of the Left Inferior Frontal Cortex Affects Social Monitoring during Motor Interactions.

Motor interactions require observing and monitoring a partner's performance as the interaction unfolds. Studies in monkeys suggest that this form of social monitoring might be mediated by the activity of the ventral premotor cortex (vPMc), a critical brain region in action observation and motor planning. Our previous fMRI studies in humans showed that the left vPMc is indeed recruited during social monitoring, but its causal role is unexplored. In three experiments, we applied online anodal or cathodal transcranial direct current stimulation over the left lateral frontal cortex during a music-like interactive task to test the hypothesis that neuromodulation of the left vPMc affects participants' performance when a partner violates the agent's expectations. Participants played short musical sequences together with a virtual partner by playing one note each in turn-taking. In 50% of the trials, the partner violated the participant's expectations by generating the correct note through an unexpected movement. During sham stimulation, the partner's unexpected behavior led to a slowdown in the participant's performance (observation-induced posterror slowing). A significant interaction with the stimulation type showed that cathodal and anodal transcranial direct current stimulation induced modulation of the observation-induced posterror slowing in opposite directions by reducing or enhancing it, respectively. Cathodal stimulation significantly reduced the effect compared to sham stimulation. No effect of neuromodulation was found when the partner behaved as expected or when the observed violation occurred within a context that was perceptually matched but noninteractive in nature. These results provide evidence for the critical causal role that the left vPMc might play in social monitoring during motor interactions, possibly through the interplay with other brain regions in the posterior medial frontal cortex.

The social relevance and the temporal constraints of motor resonance in humans.

In humans, motor resonance effects can be tracked by measuring the enhancement of corticospinal excitability by action observation. Uncovering factors driving motor resonance is crucial for optimizing action observation paradigms in experimental and clinical settings. In the present study, we deepen motor resonance properties for grasping movements. Thirty-five healthy subjects underwent an action observation task presenting right-hand grasping movements differing from their action goal. Single-pulse transcranial magnetic stimulation was applied over the left primary motor cortex at 100, 200, or 300 ms from the onset of the visual stimulus depicting the action. Motor-evoked potentials were recorded from four muscles of the right hand and forearm. Results show a muscle-specific motor resonance effect at 200 ms after movement but selectively for observing a socially relevant grasp towards another human being. This effect correlates with observers' emotional empathy scores, and it was followed by inhibition of motor resonance at 300 ms post-stimulus onset. No motor resonance facilitation emerged while observing intransitive hand movement or object grasping. This evidence highlights the social side of motor resonance and its dependency on temporal factors.

Does cognitive decline influence signing?

OBJECTIVE: The study explored the change in handwritten signature in neurodegenerative diseases by using of a rater-based approach. METHODS: Four independent observers were required to compare a pair of signatures (on average, 5 years elapsed between the two signatures) made by 103 patients (mean age 72 years) with Alzheimer's disease (AD) or frontotemporal dementia (FTD) and by 31 healthy participants (HC; mean age 73 years), judging their change according to a 0-1 rating scale (0 = similar or 1 = different). If a signature change was detected, the rater had also to report which signature features (spatial layout, omitted/added/switched letters or names, shape of letter, pen-flow) changed on the same 0-1 scale. For the AD and FTD groups, one signature was collected prior to the diagnosis of dementia, the other subsequent. RESULTS: A signature change was reported by raters in 36% of AD patients, 44% of FTD, and 17% of HC, with significant differences between both clinical groups and HC (vs. AD, p = .01; vs. FTD, p = .001). There was not a distinctive marker of the signature change (i.e., feature change) in patients with dementia. Moreover, the signature changes in neurological patients were unrelated to their clinical and demographic characteristics (age, sex, education, time elapsed between the two signatures, Mini-mental State Examination score). CONCLUSION: The findings suggest a resistance of handwritten signature in neurodegenerative diseases and in physiological aging, also suggesting that the signature may be an unreliable indicator of the cognitive status in AD and FTD, at least if subjectively evaluated.

Reversed Mirror Therapy (REMIT) after Stroke-A Proof-of-Concept Study.

In mirror training (MIT), stroke patients strive to move their hands while looking at the reflected image of the unaffected one. The recruitment of the mirror neurons and visual-proprioceptive conflict are expected to facilitate the paretic voluntary movement. Here, a reversed MIT (REMIT) is presented, which requires moving hands while looking at the reflected image of the paretic one, giving the illusion of being unable to move the unimpaired hand. This study compares MIT and REMIT on post-stroke upper-limb recovery to gain clues on the mechanism of action of mirror therapies. Eight chronic stroke patients underwent two weeks of MIT and REMIT (five sessions each) in a crossover design. Upper-limb Fugl-Meyer, Box and Block and handgrip strength tests were administered at baseline and treatments end. The strength of the mirror illusion was evaluated after each session. MIT induced a larger illusory effect. The Fugl-Meyer score improved to the same extent after both treatments. No changes occurred in the Box and Block and the handgrip tests. REMIT and MIT were equally effective on upper-limb dexterity, challenging the exclusive role of mirror neurons. Contrasting learned nonuse through an intersensory conflict might provide the rationale for both forms of mirror-based rehabilitation after stroke.

Modulating motor resonance with paired associativestimulation: Neurophysiological and behavioral outcomes.

In the human brain, paired associative stimulation (PAS), a non-invasive brain stimulation technique based on Hebbian learning principles, can be used to model motor resonance, the inner activation of an observer's motor system by action observation. Indeed, the newly developed mirror PAS (m-PAS) protocol, through the repeatedly pairing of transcranial magnetic stimulation (TMS) pulses over the primary motor cortex (M1) and visual stimuli depicting index-finger movements, allows the emergence of a new, atypical pattern of cortico-spinal excitability. In the present study, we performed two experiments to explore (a) the debated hemispheric lateralization of the action-observation network and (b) the behavioral after-effects of m-PAS, particularly concerning a core function of the MNS: automatic imitation. In Experiment 1, healthy participants underwent two sessions of m-PAS, delivered over the right and left M1. Before and after each m-PAS session, motor resonance was assessed by recording motor-evoked potentials induced by single-pulse TMS applied to the right M1 while observing contralateral (left) and ipsilateral (right) index-finger movements or static hands. In Experiment 2, participants performed an imitative compatibility task before and after the m-PAS targeting the right M1. Results showed that only m-PAS targeting the right hemisphere, non-dominant in right-handed people, induced the emergence of motor resonance for the conditioned movement, absent before the stimulation. This effect is not present when m-PAS target the M1 of the left hemisphere. Importantly, the protocol also affects behavior, modulating automatic imitation in a strictly somatotopic fashion (i.e., influencing the imitation of the conditioned finger movement). Overall, this evidence shows that the m-PAS can be used to drive new associations between the perception of actions and their corresponding motor programs, measurable both at a neurophysiological and behavioral level. At least for simple, not goal-directed, movements, the induction of motor resonance and automatic imitation effects are governed by mototopic and somatotopic rules.

Two Cases of Malingered Crime-Related Amnesia.

Amnesia is a frequent claim in major crimes, and it is estimated that the complete or partial absence of memory following a crime ranges from 25% to 50% of total cases. Although some cases may constitute a genuine form of amnesia, due to organic-neurological defects or psychological causes, and possibly combined with a dissociative or repressive coping style after an extreme experience, malingering is still fairly common in offenders. Therefore, one of the main goals in medico-legal proceedings is to find methods to determine the credibility of crime-related amnesia. At present, a number of lie and memory detection techniques can assist the forensic assessment of the reliability of declarative proof, and have been devised and improved over the past century: for example, modern polygraphs, event-related potentials, thermal imaging, functional magnetic resonance imaging, kinematic, and facial analysis. Other ad hoc psychological tests, such as the so-called Symptom Validity Test (SVT) and Performance Validity Test (PVT), as well as the autobiographical Implicit Association Test (aIAT), can also be used. To date, however, there is little evidence or case reports that document their real usefulness in forensic practice. Here, we report two cases of crime-related amnesia, whereby both defendants, who were found guilty of homicide, appeared to exhibit dissociative amnesia but where the application of SVTs, PVTs, and aIAT detected a malingered amnesia.

Quantification of retinal ganglion cell loss in patients with homonymous visual field defect due to stroke.

BACKGROUND: To quantify the degree of ganglion cell degeneration through spectral domain optical coherence tomography (SD-OCT) in adult patients with post-stroke homonymous visual field defect. METHODS: Fifty patients with acquired visual field defect due to stroke (mean age = 61 years) and thirty healthy controls (mean age = 58 years) were included. Mean deviation (MD) and pattern standard deviation (PSD), average peripapillary retinal nerve fibre layer thickness (pRNLF-AVG), average ganglion cell complex thickness (GCC-AVG), global loss volume (GLV) and focal loss volume (FLV) were measured. Patients were divided according to the damaged vascular territories (occipital vs. parieto-occipital) and stroke type (ischaemic vs. haemorrhagic). Group analysis was conducted with ANOVA and multiple regressions. RESULTS: pRNFL-AVG was significantly decreased among patients with lesions in parieto-occipital territories compared to controls and to patients with lesions in occipital territories (p = .04), with no differences with respect to stroke type. GCC-AVG, GLV and FLV differed in stroke patients and controls, regardless of stroke type and involved vascular territories. Age and elapsed time from stroke had a significant effect on pRNFL-AVG and GCC-AVG (p < .01), but not on MD and PSD. CONCLUSIONS: Reduction of SD-OCT parameters occurs following both ischaemic and haemorrhagic occipital stroke, but it is larger when the injury extends to parietal territories and increases as time since stroke increases. The size of visual field defect is unrelated to SD-OCT measurements. Macular GCC thinning appeared to be more sensitive than pRNFL in detecting retrograde retinal ganglion cell degeneration and its retinotopic pattern in stroke.

Differential Item Functioning of the Mini-BESTest Balance Measure: A Rasch Analysis Study.

The Mini-Balance Evaluation Systems Test (Mini-BESTest), a 14-item scale, has high content validity for balance assessment. This study further examines the construct validity of the Mini-BESTest with an emphasis on its measurement invariance. The Mini-BESTest was administered to 292 neurological patients in two sessions (before and after rehabilitation) and evaluated with the Rasch analysis (Many-Facet Rating Scale Model: persons, items, sessions). Categories' order and fit to the model were assessed. Next, maps, dimensionality, and differential item functioning (DIF) were examined for construct validity evaluation. DIF was inspected for several clinically important variables, including session, diagnosis, and assistive devices. Mini-BESTest items had ordered categories and fitted the Rasch model. The item map did not flag severe construct underrepresentation. The dimensionality analysis showed that another variable extraneous to balance affected the score of a few items. However, this multidimensionality had only a modest impact on measures. Session did not cause DIF. DIF for assistive devices affected six items and caused a severe measurement artefact. The measurement artefact caused by DIF for diagnosis was negligible. The Mini-BESTest returns interval measures with robust construct validity and measurement invariance. However, caution should be used when comparing Mini-BESTest measures obtained with and without assistive devices.

The effects of estradiol levels on crossmodal perception: a study on the sound induced flash illusion in healthy and menstrually related migraine individuals.

OBJECTIVE: The sound-induced flash illusion (SIFI) is a valid paradigm to study multisensorial perception. In the "fission" SIFI, multiple flashes are perceived when observing a single flash paired with two or more beeps. SIFI is largely dependent on visual and acoustic cortex excitability; in migraine, dysfunctional cortical excitability affects SIFI perception. Since estrogen peak occurring during ovulation can increase neuronal excitability, the present study aims to verify whether cortical excitability shifts linked to the menstrual cycle could influence SIFI. METHODS: In a comparative prospective study, we tested the effect of estrogens on crossmodal perception using the SIFI. We recruited 27 females in reproductive age, including 16 healthy and 11 menstrually related migraine females, testing their proneness to SIFI on day 14 (high estradiol) and day 27 (low estradiol) of menstrual cycle. RESULTS: Women on day 14 reported less flashes than on day 27 (p = 0.02) in the fission illusion, suggesting a pro-excitatory effect of estradiol on visual cortex excitability during ovulation. Moreover, we confirmed that migraine women perceived less flashes (p = 0.001) than controls, independently from cycle phase. Non-migraineurs women significantly reported more flashes on day 27 than on day 14 (p = 0.04). CONCLUSIONS: This study suggests that estradiol may influence the multisensory perception due to changes of visual cortex excitability, with high estradiol peak leading to increased visual cortical sensitivity during ovulation in non-migraineurs. Visual cortex hyperresponsiveness, here reflected by reduced SIFI, is not influenced by estradiol fluctuations in migraine women, as shown by reduced fission effects on day 14 and 27.