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 Past, Present, and Future of the Brain Imaging Data Structure (BIDS).

The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, the mechanisms by which it has been extended, and some of the challenges being addressed as it evolves. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS.

Influence of frontal-to-parietal connectivity in pseudoneglect: A cortico-cortical paired associative stimulation study.

Pseudoneglect is a set of visuospatial biases that entails a behavioral advantage for stimuli appearing in the left hemifield compared to the right one. Although right hemisphere dominance for visuospatial processing has been invoked to explain this phenomenon, its neurophysiological mechanisms are still debated, and the role of intra- and inter-hemispheric connectivity is yet to be defined. The present study explored the possibility of modulating pseudoneglect in healthy participants through a cortico-cortical paired associative stimulation protocol (ccPAS): a non-invasive brain stimulation protocol that manipulates the interplay between brain regions through the repeated, time-locked coupling of two transcranial magnetic stimulation (TMS) pulses. In the first experiment, healthy participants underwent a frontal-to-parietal (FP) and a parietal-to-frontal (PF) ccPAS. In the FP protocol, the first TMS pulse targeted the right frontal eye field (FEF), and the second pulse the right inferior parietal lobule (IPL), two critical areas for visuospatial and attentional processing. In the PF condition, the order of the pulses was reversed. In both protocols, the inter-stimulus interval (ISI) was 10 ms. Before and after stimulation, pseudoneglect was assessed with a landmark task and a manual line bisection task. A second experiment controlled for ccPAS timing dependency by testing FP-ccPAS with a longer ISI of 100 ms. Results showed that after administering the FP-ccPAS with the ISI of 10 ms, participants' leftward bias in the landmark task increased significantly, with no effects in the manual line bisection task. The other two protocols tested were ineffective. Our findings showed that ccPAS could be used to modulate pseudoneglect by exploiting frontal-to-parietal connectivity, possibly through increased top-down attentional control. FP-ccPAS could represent a promising tool to investigate connectivity properties within visuospatial and attentional networks in the healthy and as a potential rehabilitation protocol in patients suffering from severe visuospatial pathologies.

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.

Effects of transcranial magnetic stimulation (TMS) current direction and pulse waveform on cortico-cortical connectivity: A registered report TMS-EEG study.

Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs) are a promising proxy for measuring effective connectivity, that is, the directed transmission of physiological signals along cortico-cortical tracts, and for developing connectivity-based biomarkers. A crucial point is how stimulation parameters may affect TEPs, as they may contribute to the general variability of findings across studies. Here, we manipulated two TMS parameters (i.e. current direction and pulse waveform) while measuring (a) an early TEP component reflecting contralateral inhibition of motor areas, namely, M1-P15, as an operative model of interhemispheric cortico-cortical connectivity, and (b) motor-evoked potentials (MEP) for the corticospinal pathway. Our results showed that these two TMS parameters are crucial to evoke the M1-P15, influencing its amplitude, latency, and replicability. Specifically, (a) M1-P15 amplitude was strongly affected by current direction in monophasic stimulation; (b) M1-P15 latency was significantly modulated by current direction for monophasic and biphasic pulses. The replicability of M1-P15 was substantial for the same stimulation condition. At the same time, it was poor when stimulation parameters were changed, suggesting that these factors must be controlled to obtain stable single-subject measures. Finally, MEP latency was modulated by current direction, whereas non-statistically significant changes were evident for amplitude. Overall, our study highlights the importance of TMS parameters for early TEP responses recording and suggests controlling their impact in developing connectivity biomarkers from TEPs. Moreover, these results point out that the excitability of the corticospinal tract, which is commonly used as a reference to set TMS intensity, may not correspond to the excitability of cortico-cortical pathways.

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.

Targeting Default Mode Network Dysfunction in Persons at Risk of Alzheimer's Disease with Transcranial Magnetic Stimulation (NEST4AD): Rationale and Study Design.

BACKGROUND: Default mode network (DMN) dysfunction is well established in Alzheimer's disease (AD) and documented in both preclinical stages and at-risk subjects, thus representing a potential disease target. Multi-sessions of repetitive transcranial magnetic stimulation (rTMS) seem capable of modulating DMN dynamics and memory in healthy individuals and AD patients; however, the potential of this approach in at-risk subjects has yet to be tested. OBJECTIVE: This study will test the effect of rTMS on the DMN in healthy older individuals carrying the strongest genetic risk factor for AD, the Apolipoprotein E (APOE) ɛ4 allele. METHODS: We will recruit 64 older participants without cognitive deficits, 32 APOE ɛ4 allele carriers and 32 non-carriers as a reference group. Participants will undergo four rTMS sessions of active (high frequency) or sham DMN stimulation. Multimodal imaging exam (including structural, resting-state, and task functional MRI, and diffusion tensor imaging), TMS with concurrent electroencephalography (TMS-EEG), and cognitive assessment will be performed at baseline and after the stimulation sessions. RESULTS: We will assess changes in DMN connectivity with resting-state functional MRI and TMS-EEG, as well as changes in memory performance in APOE ɛ4 carriers. We will also investigate the mechanisms underlying DMN modulation through the assessment of correlations with measures of neuronal activity, excitability, and structural connectivity with multimodal imaging. CONCLUSION: The results of this study will inform on the physiological and cognitive outcomes of DMN stimulation in subjects at risk for AD and on the possible mechanisms. These results may outline the design of future non-pharmacological preventive interventions for AD.

Paired associative stimulations: Novel tools for interacting with sensory and motor cortical plasticity.

In the early 2000s, a novel non-invasive brain stimulation protocol, the paired associative stimulation (PAS), was introduced, allowing to induce and investigate Hebbian associative plasticity within the humans' motor system, with patterns resembling spike-timing-dependent plasticity properties found in cellular models. Since this evidence, PAS efficacy has been proved in healthy, and to a lesser extent, in clinical populations. Recently, novel 'modified' protocols targeting sensorimotor and crossmodal networks appeared in the literature. In the present work, we have reviewed recent advances using these 'modified' PAS protocols targeting sensory and motor cortical networks. To better categorize them, we propose a novel classification according to the nature of the peripheral and cortical stimulations (i.e., within-system, cross-systems, and cortico-cortical PAS). For each protocol of the categories mentioned above, we describe and discuss their main features, how they have been used to study and promote brain plasticity, and their advantages and disadvantages. Overall, current evidence suggests that these novel non-invasive brain stimulation protocols represent very promising tools to study the plastic properties of humans' sensorimotor and crossmodal networks, both in the healthy and in the damaged central nervous system.

Modulating Frontal Networks' Timing-Dependent-Like Plasticity With Paired Associative Stimulation Protocols: Recent Advances and Future Perspectives.

Starting from the early 2000s, paired associative stimulation (PAS) protocols have been used in humans to study brain connectivity in motor and sensory networks by exploiting the intrinsic properties of timing-dependent cortical plasticity. In the last 10 years, PAS have also been developed to investigate the plastic properties of complex cerebral systems, such as the frontal ones, with promising results. In the present work, we review the most recent advances of this technique, focusing on protocols targeting frontal cortices to investigate connectivity and its plastic properties, subtending high-order cognitive functions like memory, decision-making, attentional, or emotional processing. Overall, current evidence reveals that PAS can be effectively used to assess, enhance or depress physiological connectivity within frontal networks in a timing-dependent way, in turn modulating cognitive processing in healthy and pathological conditions.

Cross-modal involvement of the primary somatosensory cortex in visual working memory: A repetitive TMS study.

Recent literature suggests that the primary somatosensory cortex (S1), once thought to be a low-level area only modality-specific, is also involved in higher-level, cross-modal, cognitive functions. In particular, electrophysiological studies have highlighted that the cross-modal activation of this area may also extend to visual Working Memory (WM), being part of a mnemonic network specific for the temporary storage and manipulation of visual information concerning bodies and body-related actions. However, the causal recruitment of S1 in the WM network remains speculation. In the present study, by taking advantage of repetitive Transcranial Magnetic Stimulation (rTMS), we look for causal evidence that S1 is implicated in the retention of visual stimuli that are salient for this cortical area. To this purpose, in a first experiment, high-frequency (10 Hz) rTMS was delivered over S1 of the right hemisphere, and over two control sites, the right lateral occipital cortex (LOC) and the right dorsolateral prefrontal cortex (dlPFC), during the maintenance phase of a high-load delayed match-to-sample task in which body-related visual stimuli (non-symbolic hand gestures) have to be retained. In a second experiment, the specificity of S1 recruitment was deepened by using a version of the delayed match-to-sample task in which visual stimuli depict geometrical shapes (non-body related stimuli). Results show that rTMS perturbation of S1 activity leads to an enhancement of participants' performance that is selective for body-related visual stimuli; instead, the stimulation of the right LOC and dlPFC does not affect the temporary storage of body-related visual stimuli. These findings suggest that S1 may be recruited in visual WM when information to store (and recall) is salient for this area, corroborating models which suggest the existence of a dedicated mnemonic system for body-related information in which also somatosensory cortices play a key role, likely thanks to their cross-modal (visuo-tactile) properties.

Paired Associative Stimulation drives the emergence of motor resonance.

BACKGROUND: Associative plasticity, the neurophysiological bases of Hebbian learning, has been implied in the formation of the association between sensory and motor representations of actions in the Mirror Neuron System; however, such inductor role still needs empirical support. OBJECTIVE/HYPOTHESIS: We have assessed whether Paired Associative Stimulation (PAS), known to activate Hebbian associative plasticity, can induce the formation of atypical (absent in normal conditions), visuo-motor associations, reshaping motor resonance. METHODS: Healthy participants underwent a novel PAS protocol (mirror-PAS, m-PAS), during which they were exposed to repeated pairings of transcranial magnetic stimulation (TMS) applied over the right primary motor cortex (M1), time-locked with the view of index-finger movements of the right (ipsilateral) hand. In a first experiment, the inter-stimulus interval (ISI) between visual-action stimuli and TMS pulses was varied. 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, during the observation of both contralateral (left) and ipsilateral (right) index-finger movements. In the second experiment, the specificity of the m-PAS was assessed by presenting a visual stimulus depicting a non-biological movement. RESULTS: Before m-PAS, the facilitation of corticospinal excitability occurred only during the view of contralateral (with respect to the TMS side) index-finger movements. The m-PAS induced new ipsilateral motor resonance responses, indexed by atypical facilitation of corticospinal excitability by the view of ipsilateral hand movements. This effect occurred only if the associative stimulation followed the chronometry of motor control (ISI of 25 ms) and if the visual stimulus of the m-PAS depicts a biological movement (human hand action). CONCLUSIONS: The present findings provide the first empirical evidence that Hebbian learning induced by a PAS protocol shapes the visual-motor matching properties of the human Mirror Neuron System.

Touch anticipation mediates cross-modal Hebbian plasticity in the primary somatosensory cortex.

Paired associative stimulation (PAS) protocols can be used to induce Hebbian plasticity in the human brain. A modified, cross-modal version, of the PAS (cross-modal PAS, cm-PAS) has been recently developed. The cm-PAS consists in the repetitive pairings of a transcranial magnetic stimulation (TMS) pulse over the primary somatosensory cortex (S1) and a visual stimulus depicting a hand being touched; a 20 ms of inter-stimulus interval (ISI) is required to affect S1 plasticity, in turn modulating tactile acuity and somatosensory evoked potentials. The present study explores the role of anticipatory simulation in the cm-PAS efficacy, which could be responsible for such a short ISI. To this aim, we compared the effect of the original, fixed-frequency, cm-PAS to that of a jittered version, in which the time interval between trials was not steady but jittered, hence avoiding the anticipation of the upcoming visual-touch stimulus. Moreover, in the jittered PAS, the ISI between the paired stimulations was varied: it could match the early, somatosensory-driven, activation of S1 (20 ms), or the mirror recruitment of S1 by touch observation (150 ms). Results showed that tactile acuity is enhanced by the fixed-frequency cm-PAS, with an ISI of 20 ms between paired stimulation (visual-touch stimulus and TMS pulse over S1), and also by the jittered cm-PAS but only if the ISI is of 150 ms. These findings suggest that the cm-PAS with a jittered frequency, by preventing an anticipatory pre-activation of S1, delays the timing of the interaction between the visual-touch stimulus and the cortical pulse. On a broader perspective, our study highlights the possible involvement of sensory anticipation, likely through mirror-like simulation mechanisms, in tactile mirroring, as well as its influence of the optimal interval between the afferent and the magnetic pulse during PAS protocols.

Hebbian associative plasticity in the visuo-tactile domain: A cross-modal paired associative stimulation protocol.

We developed and assessed the effects of a novel cross-modal protocol aimed at inducing associative (Hebbian-like) plasticity in the somatosensory cortical system through vision. Associative long-term potentiation can be induced in the primary somatosensory cortex (S1) by means of paired associative stimulation (PAS), in which a peripheral electrical stimulation of the median nerve is repeatedly paired with a transcranial magnetic stimulation (TMS) pulse over S1. Considering the mirror proprieties of S1, the cross-modal PAS (cm-PAS) consists of repetitive observation of bodily tactile stimulations, paired with TMS pulses over the contralateral S1. Through three experiments in healthy participants, we demonstrate that the cm-PAS is able to induce excitatory plastic effects with functional significance in S1, improving somatosensory processing at both behavioral (tactile acuity) and neurophysiological (somatosensory-evoked potentials) levels. The plastic effects induced by cm-PAS depend on the interval (20 ms) between the visual stimulus and the magnetic pulse, the targeted cortical site (S1), and the tactile content of the visual stimulus, which must represent a touch event. Such specificity implies the involvement of cross-modal, mirror-like, mechanisms in S1, which are able to visually promote associative synaptic plasticity in S1 likely through the recruitment of predictive coding processes.

Keeping order in the brain: The supramarginal gyrus and serial order in short-term memory.

A wide range of human activities are performed sequentially in few seconds. We need to maintain a correct temporal order of words in language, movements in actions, directions in navigation, etc. Therefore, it is plausible, in a more economical perspective, that our brain is equipped with a dedicated mechanism for storing a temporal sequence for a short time. To investigate it, we run four TMS experiments, in which participants performed different short-term memory tasks, i.e., three (verbal, spatial, motor) requiring maintenance of an ordered sequence and one (visual) of a static pattern. We demonstrated, for the first time, that the left supramarginal gyrus is one of the key nodes of the STM network involved in retaining an abstract representation of serial order information, independently from the content information, namely the nature of the item to be remembered, which instead is stored separately.