Prediction of rehabilitation induced motor recovery after stroke using a multi-dimensional and multi-modal approach.

Background: Stroke is a debilitating disease affecting millions of people worldwide. Despite the survival rate has significantly increased over the years, many stroke survivors are left with severe impairments impacting their quality of life. Rehabilitation programs have proved to be successful in improving the recovery process. However, a reliable model of sensorimotor recovery and a clear identification of predictive markers of rehabilitation-induced recovery are still needed. This article introduces the cross-modality protocols designed to investigate the rehabilitation treatment's effect in a group of stroke survivors. Methods/design: A total of 75 stroke patients, admitted at the IRCCS San Camillo rehabilitation Hospital in Venice (Italy), will be included in this study. Here, we describe the rehabilitation programs, clinical, neuropsychological, and physiological/imaging [including electroencephalography (EEG), transcranial magnetic stimulation (TMS), and magnetic resonance imaging (MRI) techniques] protocols set up for this study. Blood collection for the characterization of predictive biological biomarkers will also be taken. Measures derived from data acquired will be used as candidate predictors of motor recovery. Discussion/summary: The integration of cutting-edge physiological and imaging techniques, with clinical and cognitive assessment, dose of rehabilitation and biological variables will provide a unique opportunity to define a predictive model of recovery in stroke patients. Taken together, the data acquired in this project will help to define a model of rehabilitation induced sensorimotor recovery, with the final aim of developing personalized treatments promoting the greatest chance of recovery of the compromised functions.

Stuttering-Like Dysfluencies as a Consequence of Long COVID-19.

PURPOSE: We present two patients who developed neurogenic stuttering after long COVID-19 related to SARS-CoV-2 infection. METHODS AND RESULTS: Both patients experienced both physical (e.g., fatigue) and cognitive difficulties, which led to impaired function of attention, lexical retrieval, and memory consolidation. Both patients had new-onset stuttering-like speech dysfluencies: Blocks and repetitions were especially evident at the initial part of words and sentences, sometimes accompanied by effortful and associated movements (e.g., facial grimaces and oro-facial movements). Neuropsychological evaluations confirmed the presence of difficulties in cognitive tasks, while neurophysiological evaluations (i.e., electroencephalography) suggested the presence of "slowed" patterns of brain activity. Neurogenic stuttering and cognitive difficulties were evident for 4-5 months after negativization of SARS-CoV-2 nasopharyngeal swab, with gradual improvement and near-to-complete recovery. CONCLUSIONS: It is now evident that SARS-CoV-2 infection may significantly involve the central nervous system, also resulting in severe and long-term consequences, even if the precise mechanisms are still unknown. In the present report, long COVID-19 resulted in neurogenic stuttering, as the likely consequence of a "slowed" metabolism of (pre)frontal and sensorimotor brain regions (as suggested by the present and previous clinical evidence). As a consequence, the pathophysiological mechanisms related to the appearance of neurogenic stuttering have been hypothesized, which help to better understand the broader and possible neurological consequences of COVID-19.

Inefficient speech-motor control affects predictive speech comprehension: atypical electrophysiological correlates in stuttering.

Listeners predict upcoming information during language comprehension. However, how this ability is implemented is still largely unknown. Here, we tested the hypothesis proposing that language production mechanisms have a role in prediction. We studied 2 electroencephalographic correlates of predictability during speech comprehension-pre-target alpha-beta (8-30 Hz) power decrease and the post-target N400 event-related potential effect-in a population with impaired speech-motor control, i.e. adults who stutter (AWS), compared to typically fluent adults (TFA). Participants listened to sentences that could either constrain towards a target word or not, modulating its predictability. As a complementary task, participants also performed context-driven word production. Compared to TFA, AWS not only displayed atypical neural responses in production, but, critically, they showed a different pattern also in comprehension. Specifically, while TFA showed the expected pre-target power decrease, AWS showed a power increase in frontal regions, associated with speech-motor control. In addition, the post-target N400 effect was reduced for AWS with respect to TFA. Finally, we found that production and comprehension power changes were positively correlated in TFA, but not in AWS. Overall, the results support the idea that processes and neural structures prominently devoted to speech planning also support prediction during speech comprehension.

Speech Fluency Improvement in Developmental Stuttering Using Non-invasive Brain Stimulation: Insights From Available Evidence.

Developmental stuttering (DS) is a disturbance of the normal rhythm of speech that may be interpreted as very debilitating in the most affected cases. Interventions for DS are historically based on the behavioral modifications of speech patterns (e.g., through speech therapy), which are useful to regain a better speech fluency. However, a great variability in intervention outcomes is normally observed, and no definitive evidence is currently available to resolve stuttering, especially in the case of its persistence in adulthood. In the last few decades, DS has been increasingly considered as a functional disturbance, affecting the correct programming of complex motor sequences such as speech. Compatibly, understanding of the neurophysiological bases of DS has dramatically improved, thanks to neuroimaging, and techniques able to interact with neural tissue functioning [e.g., non-invasive brain stimulation (NIBS)]. In this context, the dysfunctional activity of the cortico-basal-thalamo-cortical networks, as well as the defective patterns of connectivity, seems to play a key role, especially in sensorimotor networks. As a consequence, a direct action on the functionality of "defective" or "impaired" brain circuits may help people who stutter to manage dysfluencies in a better way. This may also "potentiate" available interventions, thus favoring more stable outcomes of speech fluency. Attempts aiming at modulating (and improving) brain functioning of people who stutter, realized by using NIBS, are quickly increasing. Here, we will review these recent advancements being applied to the treatment of DS. Insights will be useful not only to assess whether the speech fluency of people who stutter may be ameliorated by acting directly on brain functioning but also will provide further suggestions about the complex and dynamic pathophysiology of DS, where causal effects and "adaptive''/''maladaptive" compensation mechanisms may be strongly overlapped. In conclusion, this review focuses future research toward more specific, targeted, and effective interventions for DS, based on neuromodulation of brain functioning.

Developmental stuttering and the role of the supplementary motor cortex.

Developmental stuttering is a frequent neurodevelopmental disorder with a complex neurobiological basis. Robust neural markers of stuttering include imbalanced activity of speech and motor related brain regions, and their impaired structural connectivity. The dynamic interaction of cortical regions is regulated by the cortico-basal ganglia-thalamo-cortical system with the supplementary motor area constituting a crucial cortical site. The SMA integrates information from different neural circuits, and manages information about motor programs such as self-initiated movements, motor sequences, and motor learning. Abnormal functioning of SMA is increasingly reported in stuttering, and has been recently indicated as an additional "neural marker" of DS: anatomical and functional data have documented abnormal structure and activity of the SMA, especially in motor and speech networks. Its connectivity is often impaired, especially when considering networks of the left hemisphere. Compatibly, recent data suggest that, in DS, SMA is part of a poorly synchronized neural network, thus resulting in a likely substrate for the appearance of DS symptoms. However, as evident when considering neural models of stuttering, the role of SMA has not been fully clarified. Herein, the available evidence is reviewed, which highlights the role of the SMA in DS as a neural "hub", receiving and conveying altered information, thus "gating" the release of correct or abnormal motor plans.

Effect of muscular activation on surrounding motor networks in developmental stuttering: A TMS study.

Previous studies regarding developmental stuttering (DS) suggest that motor neural networks are strongly affected. Transcranial magnetic stimulation (TMS) was used to investigate neural activation of the primary motor cortex in DS during movement execution, and the influence of muscle representations involved in movements on "surrounding" ones. TMS was applied over the contralateral abductor digiti minimi (ADM) motor representation, at rest and during the movement of homologue first dorsal interosseous muscles (tonic contraction, phasic movements cued by acoustic signalling, and "self-paced" movements). Results highlighted a lower cortico-spinal excitability of ADM in the left hemisphere of stutterers, and an enhanced intracortical inhibition in their right motor cortex (in comparison to fluent speakers). Abnormal intracortical functioning was especially evident during phasic contractions cued by "external" acoustic signals. An exaggerated inhibition of muscles not directly involved in intended movements, in stuttering, may be useful to obtain more efficient motor control. This was stronger during contractions cued by "external" signals, highlighting mechanisms likely used by stutterers during fluency-evoking conditions.

Stuttering as a matter of delay in neural activation: A combined TMS/EEG study.

OBJECTIVE: Brain dynamics in developmental stuttering (DS) are not well understood. The supplementary motor area (SMA) plays a crucial role, since it communicates with regions related to planning/execution of movements, and with sub-cortical regions involved in paced/voluntary acts (such as speech). We used TMS combined with EEG to shed light on connections in DS, stimulating the SMA. METHODS: TMS/EEG was recorded in adult DS and fluent speakers (FS), stimulating the SMA during rest. TMS-evoked potentials and source distribution were evaluated. RESULTS: Compared to FS, stutterers showed lower activity of neural sources in early time windows: 66-82 ms in SMA, and 91-102 ms in the left inferior frontal cortex and left inferior parietal lobule. Stutterers, however, showed higher activations in later time windows (i.e. from 260-460 ms), in temporal/premotor regions of the right hemisphere. CONCLUSIONS: These findings represent the functional counterpart to known white matter and cortico-basal-thalamo-cortical abnormalities in DS. They also explain how white matter abnormalities and cortico-basal-thalamo-cortical dysfunctions may be associated in DS. Finally, a mechanism is proposed in which compensatory activity of the non-dominant (right) hemisphere is recruited. SIGNIFICANCE: DS may be a disorder of neural timing that appears to be delayed compared to FS; new mechanisms that support stuttering symptoms are inferred; the SMA may be a promising target for neuro-rehabilitation.

Stuttering-like hesitation in speech during acute/post-acute phase of immune-mediated encephalitis.

PURPOSE: Neurogenic stuttering may be evident after a lesion/dysfunction of wider neural networks. Here we present a case of acquired stuttering as the consequence of immune-mediated encephalitis. METHODS: The case of a 71-year old male who complained about the progressive onset of stuttering and disequilibrium as the consequence of immune-mediated encephalitis, is here reported. Administration of corticosteroid methylprednisolone was useful to recover from impairments. An in depth analysis of the electroencephalography (relative power of brain rhythms and source localization) during different phases of the disease/treatment was also realized. RESULTS: The patient showed a stuttering-like slowed speech with blocks and repetitions, especially at the beginning of words/sentences, with associated movements of the oro-facial muscles. Speech and general motor skills resulted slowed in their preparation/execution phases. Electroencephalography showed a "slowed" pattern, with delta/theta waves mainly in the prefrontal cortex and in sensorimotor networks. CONCLUSION: This case reports a probable immune-mediated encephalitis that resulted in acquired stuttering. The effect of "slowed" oscillatory brain activity on motor skills requesting sequencing and fine coordination (e.g. speech) could result in less "synchronized" systems, easily prone to disruptions.

Separating the Idea from the Action: A sLORETA Study.

Simple imaginary movements activate similar cortical and subcortical areas to actual movements, chiefly in the sensory-motor network. However, only a few studies also examined the imagery of more skilful movements such as reaching. Ten volunteers performed reaching movements or imagined the same movements. EEG was simultaneously recorded and analysed with sLORETA, which compared the preparation for actual and imagined reaching with respect to their baseline and between tasks. Major differences between them were found at three time intervals after target presentation, always in favour of the actual reaching condition. The first one was from 160 to 220 msec in the frontal and parietal regions. The second difference was evident from 220 to 320 msec in the premotor cortex. The third difference was evident from 320 msec, mainly in the perirolandic region. Also, the anterior and posterior cingulate cortices were widely involved, in both tasks. We suggest the existence of two separate systems which may work together during actual reaching programming. The first one involves structures such as the premotor cortex, supplementary motor area and primary motor cortex, together with the parietal and occipital cortex. This system may integrate extrinsic target coordinates with proprioceptive information from the reaching arm and pre-stored programs in the associative motor cortex. It is activated strongly and involves more cortical areas in actual than imagined reaching. The second system, common to both tasks, involves anterior and posterior cingulate cortices, with the possible role of contributing awareness and focusing the various components of the process.

Altered Modulation of Silent Period in Tongue Motor Cortex of Persistent Developmental Stuttering in Relation to Stuttering Severity.

Motor balance in developmental stuttering (DS) was investigated with Transcranial Magnetic Stimulation (TMS), with the aim to define novel neural markers of persistent DS in adulthood. Eleven DS adult males were evaluated with TMS on tongue primary motor cortex, compared to 15 matched fluent speakers, in a "state" condition (i.e. stutterers vs. fluent speakers, no overt stuttering). Motor and silent period thresholds (SPT), recruitment curves, and silent period durations were acquired by recording tongue motor evoked potentials. Tongue silent period duration was increased in DS, especially in the left hemisphere (P<0.05; Hedge's g or Cohen's dunbiased = 1.054, i.e. large effect size), suggesting a "state" condition of higher intracortical inhibition in left motor cortex networks. Differences in motor thresholds (different excitatory/inhibitory ratios in DS) were evident, as well as significant differences in SPT. In fluent speakers, the left hemisphere may be marginally more excitable than the right one in motor thresholds at lower muscular activation, while active motor thresholds and SPT were higher in the left hemisphere of DS with respect to the right one, resulting also in a positive correlation with stuttering severity. Pre-TMS electromyography data gave overlapping evidence. Findings suggest the existence of a complex intracortical balance in DS tongue primary motor cortex, with a particular interplay between excitatory and inhibitory mechanisms, also in neural substrates related to silent periods. Findings are discussed with respect to functional and structural impairments in stuttering, and are also proposed as novel neural markers of a stuttering "state" in persistent DS, helping to define more focused treatments (e.g. neuro-modulation).

Long-range neural activity evoked by premotor cortex stimulation: a TMS/EEG co-registration study.

The premotor cortex is one of the fundamental structures composing the neural networks of the human brain. It is implicated in many behaviors and cognitive tasks, ranging from movement to attention and eye-related activity. Therefore, neural circuits that are related to premotor cortex have been studied to clarify their connectivity and/or role in different tasks. In the present work, we aimed to investigate the propagation of the neural activity evoked in the dorsal premotor cortex using transcranial magnetic stimulation/electroencephalography (TMS/EEG). Toward this end, interest was focused on the neural dynamics elicited in long-ranging temporal and spatial networks. Twelve healthy volunteers underwent a single-pulse TMS protocol in a resting condition with eyes closed, and the evoked activity, measured by EEG, was compared to a sham condition in a time window ranging from 45 ms to about 200 ms after TMS. Spatial and temporal investigations were carried out with sLORETA. TMS was found to induce propagation of neural activity mainly in the contralateral sensorimotor and frontal cortices, at about 130 ms after delivery of the stimulus. Different types of analyses showed propagated activity also in posterior, mainly visual, regions, in a time window between 70 and 130 ms. Finally, a likely "rebounding" activation of the sensorimotor and frontal regions, was observed in various time ranges. Taken together, the present findings further characterize the neural circuits that are driven by dorsal premotor cortex activation in healthy humans.

A multimenu system based on the P300 component as a time saving procedure for communication with a brain-computer interface.

The present study investigates a Brain-Computer Interface (BCI) spelling procedure based on the P300 evoked potential. It uses a small matrix of words arranged in a tree-shaped organization ("multimenu"), and allows the user to build phrases one word at a time, instead of letter by letter. Experiments were performed in two sessions on a group of seven healthy volunteers. In the former, the "multimenu" was tested with a total of 60 choices: 30 "externally-imposed" selections and 30 "free-choice" selections. In the latter, 3 × 3 matrices were compared with 6 × 6 matrices. Each matrix was composed of letters or words, for a total of four matrices. Differences in classifier accuracy, bit rate and amplitude of the evoked P300 were evaluated. Average accuracy in all subjects was 87% with no differences between the selection methods. The 3 × 3 "multimenu" obtained the same level of classifier accuracy as the 6 × 6 matrices, even with a significantly lower amplitude of the P300. Bit rate was increased when using the 3 × 3 matrices compared to the 6 × 6 ones. The "multimenu" system was equally effective, but faster than conventional, letter-based matrices. By improving the speed of communication, this method can be of help to patients with severe difficulties in communication.

Motor excitability evaluation in developmental stuttering: a transcranial magnetic stimulation study.

INTRODUCTION: Developmental stuttering (DS) is viewed as a motor speech-specific disorder, although several lines of research suggest that DS is a symptom of a broader motor disorder. We investigated corticospinal excitability in adult DS and normal speakers. METHODS: Transcranial magnetic stimulation (TMS) was administered over left/right hand representation of the motor cortex while recording motor evoked potentials (MEPs) from the contralateral first dorsal interosseous (FDI) muscle. Resting, active motor thresholds, silent period threshold and duration were measured. A stimulus-response curve at resting was also obtained to evaluate MEP amplitudes. RESULTS: Lower corticospinal responses in the left hemisphere of DS were found, as indicated by a reduction of peak-to-peak MEP amplitudes compared to normal speakers. CONCLUSIONS: This provides further evidence that DS may be a general motor deficit that also involves motor non-speech-related structures. Moreover, our results confirm that DS may be related to left hemisphere hypoactivation and/or lower left hemisphere dominance. The present data and protocol may be useful for diagnosis of subtypes of DS that may benefit from pharmacological treatment by targeting the general level of cortical excitability.

Transcranial magnetic stimulation and preparation of visually-guided reaching movements.

To better define the neural networks related to preparation of reaching, we applied transcranial magnetic stimulation (TMS) to the lateral parietal and frontal cortex. TMS did not evoke effects closely related to preparation of reaching, suggesting that neural networks already identified by our group are not larger than previously thought. We also replicated previous TMS/EEG data by applying TMS to the parietal cortex: new analyses were performed to better support reliability of already reported findings (Zanon et al., 2010; Brain Topography 22, 307-317). We showed the existence of neural circuits ranging from posterior to frontal regions of the brain after the stimulation of parietal cortex, supporting the idea of strong connections among these areas and suggesting their possible temporal dynamic. Connection with ventral stream was confirmed. The present work helps to define those areas which are involved in preparation of natural reaching in humans. They correspond to parieto-occipital, parietal and premotor medial regions of the left hemisphere, i.e., the contralateral one with respect to the moving hand, as suggested by previous studies. Behavioral data support the existence of a discrete stream involved in reaching. Besides the serial flow of activation from posterior to anterior direction, a parallel elaboration of information among parietal and premotor areas seems also to exist. Present cortico-cortical interactions (TMS/EEG experiment) show propagation of activity to frontal, temporal, parietal and more posterior regions, exhibiting distributed communication among various areas in the brain. The neural system highlighted by TMS/EEG experiments is wider with respect to the one disclosed by the TMS behavioral approach. Further studies are needed to unravel this paucity of overlap. Moreover, the understanding of these mechanisms is crucial for the comprehension of response inhibition and changes in prepared actions, which are common behaviors in everyday life.

Tongue corticospinal modulation during attended verbal stimuli: priming and coarticulation effects.

Humans perceive continuous speech through interruptions or brief noise bursts cancelling entire phonemes. This robust phenomenon has been classically associated with mechanisms of perceptual restoration. In parallel, recent experimental evidence suggests that the motor system may actively participate in speech perception, even contributing to phoneme discrimination. In the present study we intended to verify if the motor system has a specific role in speech perceptual restoration as well. To this aim we recorded tongue corticospinal excitability during phoneme expectation induced by contextual information. Results showed that phoneme expectation determines an involvement of the individual's motor system specifically implicated in the production of the attended phoneme, exactly as it happens during actual listening of that phoneme, suggesting the presence of a speech imagery-like process. Very interestingly, this motoric phoneme expectation is also modulated by subtle coarticulation cues of which the listener is not consciously aware. Present data indicate that the rehearsal of a specific phoneme requires the contribution of the motor system exactly as it happens during the rehearsal of actions executed by the limbs, and that this process is abolished when an incongruent phonemic cue is presented, as similarly occurs during observation of anomalous hand actions. We propose that altogether these effects indicate that during speech listening an attentional-like mechanism driven by the motor system, based on a feed-forward anticipatory mechanism constantly verifying incoming information, is working allowing perceptual restoration.

Vocal pitch discrimination in the motor system.

Speech production can be broadly separated into two distinct components: Phonation and Articulation. These two aspects require the efficient control of several phono-articulatory effectors. Speech is indeed generated by the vibration of the vocal-folds in the larynx (F0) followed by ''filtering" by articulators, to select certain resonant frequencies out of that wave (F1, F2, F3, etc.). Recently it has been demonstrated that the motor representation of articulators (lips and tongue) participates in the discrimination of articulatory sounds (lips- and tongue-related speech sounds). Here we investigate whether the results obtained on articulatory sounds discrimination could be extended to phonation by applying a dual-pulse TMS protocol while subjects had to discriminate F0-shifted vocal utterances [a]. Stimulation over the larynx motor representation, compared to the control site (tongue/lips motor cortex), induced a reduction in RT for stimuli including a subtle pitch shift. We demonstrate that vocal pitch discrimination, in analogy with the articulatory component, requires the contribution of the motor system and that this effect is somatotopically organized.