EMG-based prediction of step direction for a better control of lower limb wearable devices.

BACKGROUND AND OBJECTIVES: Lower-limb wearable devices can significantly improve the quality of life of subjects suffering from debilitating conditions, such as amputations, neurodegenerative disorders, and stroke-related impairments. Current control approaches, limited to forward walking, fall short of replicating the complexity of human locomotion in complex environments, such as uneven terrains or crowded places. Here we propose a high-level controller based on two Support Vector Machines exploiting four surface electromyography (EMG) signals of the thigh muscles to detect the onset (Toe-off intention decoder) and the direction (Directional EMG decoder) of the upcoming step. METHODS AND MATERIALS: We validated a preliminary version of the approach by acquiring EMG signals from ten healthy subjects, performing steps in four directions (forward, backward, right, and left), in three different settings (ground-level walking, stairs, and ramps), and in both steady-state and static conditions. Both the Toe-off intention and Directional EMG decoders have been tested with a 5-fold cross-validation repeated five times, using linear and radial-basis-function kernels, and by changing the classification output timing, from 200 ms before to 50 ms after the toe-off. RESULTS: The Toe-off intention decoder reached a median accuracy of 83.34 % (interquartile range (IQR): 6.48) and specificity of 92.72 % (IQR: 3.62) in its radial-basis-function version, while the Directional EMG decoder's median accuracy ranged between 73.92 % (IQR: 5.8), 200 ms before the toe-off, to 92.91 % (IQR: 4.11), 50 ms after the toe-off, with the radial-basis-function kernel implementation. For both the Toe-off intention and Directional EMG decoders the radial-basis-function version achieved better performances than the linear one (Wilcoxon signed rank test, p < 0.05). CONCLUSIONS AND SIGNIFICANCE: The combination of the two decoders proved to be a promising solution to detect the step initiation and classify its direction, paving the way for wearable devices with a broader range of movements and more degrees of freedom, ultimately promoting usability in uncontrolled settings and better reactions to external perturbations. Additionally, the encumbrance of the setup is limited to the thigh of the leg of interest, which simplifies the implementation in compact devices, concurrently limiting the sensors worn by the subject.

An open computational toolbox to analyze multi- and single-unit sympathetic nerve activity in microneurography.

Microelectrode recordings from human peripheral and cranial nerves provide a means to study both afferent and efferent axonal signals at different levels of detail, from multi- to single-unit activity. Their analysis can lead to advancements both in diagnostic and in the understanding of the genesis of neural disorders. However, most of the existing computational toolboxes for the analysis of microneurographic recordings are limited in scope or not open-source. Additionally, conventional burst-based metrics are not suited to analyze pathological conditions and are highly sensitive to distance of the microelectrode tip from the active axons. To address these challenges, we developed an open-source toolbox that offers advanced analysis capabilities for studying neuronal reflexes and physiological responses to peripheral nerve activity. Our toolbox leverages the observation of temporal sequences of action potentials within inherently cyclic signals, introducing innovative methods and indices to enhance analysis accuracy. Importantly, we have designed our computational toolbox to be accessible to novices in biomedical signal processing. This may include researchers and professionals in healthcare domains, such as clinical medicine, life sciences, and related fields. By prioritizing user-friendliness, our software application serves as a valuable resource for the scientific community, allowing to extract advanced metrics of neural activity in short time and evaluate their impact on other physiological variables in a consistent and standardized manner, with the final aim to widen the use of microneurography among researchers and clinicians.

A Model with Dopamine Depletion in Basal Ganglia and Cerebellum Predicts Changes in Thalamocortical Beta Oscillations.

Parkinsonism is presented as a motor syndrome characterized by rigidity, tremors, and bradykinesia, with Parkinson's disease (PD) being the predominant cause. The discovery that those motor symptoms result from the death of dopaminergic cells in the substantia nigra led to focus most of parkinsonism research on the basal ganglia (BG). However, recent findings point to an active involvement of the cerebellum in this motor syndrome. Here, we have developed a multiscale computational model of the rodent brain's BG-cerebellar network. Simulations showed that a direct effect of dopamine depletion on the cerebellum must be taken into account to reproduce the alterations of neural activity in parkinsonism, particularly the increased beta oscillations widely reported in PD patients. Moreover, dopamine depletion indirectly impacted spike-time-dependent plasticity at the parallel fiber-Purkinje cell synapses, degrading associative motor learning as observed in parkinsonism. Overall, these results suggest a relevant involvement of cerebellum in parkinsonism associative motor symptoms.

Understanding the Role of Self-Attention in a Transformer Model for the Discrimination of SCD From MCI Using Resting-State EEG.

The identification of EEG biomarkers to discriminate Subjective Cognitive Decline (SCD) from Mild Cognitive Impairment (MCI) conditions is a complex task which requires great clinical effort and expertise. We exploit the self-attention component of the Transformer architecture to obtain physiological explanations of the model's decisions in the discrimination of 56 SCD and 45 MCI patients using resting-state EEG. Specifically, an interpretability workflow leveraging attention scores and time-frequency analysis of EEG epochs through Continuous Wavelet Transform is proposed. In the classification framework, models are trained and validated with 5-fold cross-validation and evaluated on a test set obtained by selecting 20% of the total subjects. Ablation studies and hyperparameter tuning tests are conducted to identify the optimal model configuration. Results show that the best performing model, which achieves acceptable results both on epochs' and patients' classification, is capable of finding specific EEG patterns that highlight changes in the brain activity between the two conditions. We demonstrate the potential of attention weights as tools to guide experts in understanding which disease-relevant EEG features could be discriminative of SCD and MCI.

Bioelectronic modulation of carotid sinus nerve to treat type 2 diabetes: current knowledge and future perspectives.

Bioelectronic medicine are an emerging class of treatments aiming to modulate body nervous activity to correct pathological conditions and restore health. Recently, it was shown that the high frequency electrical neuromodulation of the carotid sinus nerve (CSN), a small branch of the glossopharyngeal nerve that connects the carotid body (CB) to the brain, restores metabolic function in type 2 diabetes (T2D) animal models highlighting its potential as a new therapeutic modality to treat metabolic diseases in humans. In this manuscript, we review the current knowledge supporting the use of neuromodulation of the CSN to treat T2D and discuss the future perspectives for its clinical application. Firstly, we review in a concise manner the role of CB chemoreceptors and of CSN in the pathogenesis of metabolic diseases. Secondly, we describe the findings supporting the potential therapeutic use of the neuromodulation of CSN to treat T2D, as well as the feasibility and reversibility of this approach. A third section is devoted to point up the advances in the neural decoding of CSN activity, in particular in metabolic disease states, that will allow the development of closed-loop approaches to deliver personalized and adjustable treatments with minimal side effects. And finally, we discuss the findings supporting the assessment of CB activity in metabolic disease patients to screen the individuals that will benefit therapeutically from this bioelectronic approach in the future.

Personalized modeling of Alzheimer's disease progression estimates neurodegeneration severity from EEG recordings.

INTRODUCTION: Early identification of Alzheimer's disease (AD) is necessary for a timely onset of therapeutic care. However, cortical structural alterations associated with AD are difficult to discern. METHODS: We developed a cortical model of AD-related neurodegeneration accounting for slowing of local dynamics and global connectivity degradation. In a monocentric study we collected electroencephalography (EEG) recordings at rest from participants in healthy (HC, n = 17), subjective cognitive decline (SCD, n = 58), and mild cognitive impairment (MCI, n = 44) conditions. For each patient, we estimated neurodegeneration model parameters based on individual EEG recordings. RESULTS: Our model outperformed standard EEG analysis not only in discriminating between HC and MCI conditions (F1 score 0.95 vs 0.75) but also in identifying SCD patients with biological hallmarks of AD in the cerebrospinal fluid (recall 0.87 vs 0.50). DISCUSSION: Personalized models could (1) support classification of MCI, (2) assess the presence of AD pathology, and (3) estimate the risk of cognitive decline progression, based only on economical and non-invasive EEG recordings. Highlights: Personalized cortical model estimating structural alterations from EEG recordings.Discrimination of Mild Cognitive Impairment (MCI) and Healthy (HC) subjects (95%)Prediction of biological markers of Alzheimer's in Subjective Decline (SCD) Subjects (87%)Transition correctly predicted for 3/3 subjects that converted from SCD to MCI after 1y.

Rodents' visual gamma as a biomarker of pathological neural conditions.

Neural gamma oscillations (indicatively 30-100 Hz) are ubiquitous: they are associated with a broad range of functions in multiple cortical areas and across many animal species. Experimental and computational works established gamma rhythms as a global emergent property of neuronal networks generated by the balanced and coordinated interaction of excitation and inhibition. Coherently, gamma activity is strongly influenced by the alterations of synaptic dynamics which are often associated with pathological neural dysfunctions. We argue therefore that these oscillations are an optimal biomarker for probing the mechanism of cortical dysfunctions. Gamma oscillations are also highly sensitive to external stimuli in sensory cortices, especially the primary visual cortex (V1), where the stimulus dependence of gamma oscillations has been thoroughly investigated. Gamma manipulation by visual stimuli tuning is particularly easy in rodents, which have become a standard animal model for investigating the effects of network alterations on gamma oscillations. Overall, gamma in the rodents' visual cortex offers an accessible probe on dysfunctional information processing in pathological conditions. Beyond vision-related dysfunctions, alterations of gamma oscillations in rodents were indeed also reported in neural deficits such as migraine, epilepsy and neurodegenerative or neuropsychiatric conditions such as Alzheimer's, schizophrenia and autism spectrum disorders. Altogether, the connections between visual cortical gamma activity and physio-pathological conditions in rodent models underscore the potential of gamma oscillations as markers of neuronal (dys)functioning.

Mapping dysfunctional circuits in the frontal cortex using deep brain stimulation.

Frontal circuits play a critical role in motor, cognitive and affective processing, and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)functions remains largely elusive. We studied 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregated the frontal cortex into circuits that had become dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to frontal, ranging from interconnections with sensorimotor cortices in dystonia, the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairments in the human brain.

Neurophysiological underpinnings of an intensive protocol for upper limb motor recovery in subacute and chronic stroke patients.

BACKGROUND: Upper limb (UL) motor impairment following stroke is a leading cause of functional limitations in activities of daily living. Robot-assisted therapy supports rehabilitation, but how its efficacy and the underlying neural mechanisms depend on the time after stroke is yet to be assessed. AIM: We investigated the response to an intensive protocol of robot-assisted rehabilitation in sub-acute and chronic stroke patients, by analyzing the underlying changes in clinical scores, electroencephalography (EEG) and end-effector kinematics. We aimed at identifying neural correlates of the participants' upper limb motor function recovery, following an intensive 2-week rehabilitation protocol. DESIGN: Prospective cohort study. SETTING: Inpatients and outpatients from the Neurorehabilitation Unit of Pisa University Hospital, Italy. POPULATION: Sub-acute and chronic stroke survivors. METHODS: Thirty-one stroke survivors (14 sub-acute, 17 chronic) with mild-to-moderate UL paresis were enrolled. All participants underwent ten rehabilitative sessions of task-oriented exercises with a planar end-effector robotic device. All patients were evaluated with the Fugl-Meyer Assessment Scale and the Wolf Motor Function Test, at recruitment (T0), end-of-treatment (T1), and one-month follow-up (T2). Along with clinical scales, kinematic parameters and quantitative EEG were collected for each patient. Kinematics metrics were related to velocity, acceleration and smoothness of the movement. Relative power in four frequency bands was extracted from the EEG signals. The evolution over time of kinematic and EEG features was analyzed, in correlation with motor recovery. RESULTS: Both groups displayed significant gains in motility after treatment. Sub-acute patients displayed more pronounced clinical improvements, significant changes in kinematic parameters, and a larger increase in Beta-band in the motor area of the affected hemisphere. In both groups these improvements were associated to a decrease in the Delta-band of both hemispheres. Improvements were retained at T2. CONCLUSIONS: The intensive two-week rehabilitation protocol was effective in both chronic and sub-acute patients, and improvements in the two groups shared similar dynamics. However, stronger cortical and behavioral changes were observed in sub-acute patients suggesting different reorganizational patterns. CLINICAL REHABILITATION IMPACT: This study paves the way to personalized approaches to UL motor rehabilitation after stroke, as highlighted by different neurophysiological modifications following recovery in subacute and chronic stroke patients.

PRedicting the EVolution of SubjectIvE Cognitive Decline to Alzheimer's Disease With machine learning: the PREVIEW study protocol.

BACKGROUND: As disease-modifying therapies (DMTs) for Alzheimer's disease (AD) are becoming a reality, there is an urgent need to select cost-effective tools that can accurately identify patients in the earliest stages of the disease. Subjective Cognitive Decline (SCD) is a condition in which individuals complain of cognitive decline with normal performances on neuropsychological evaluation. Many studies demonstrated a higher prevalence of Alzheimer's pathology in patients diagnosed with SCD as compared to the general population. Consequently, SCD was suggested as an early symptomatic phase of AD. We will describe the study protocol of a prospective cohort study (PREVIEW) that aim to identify features derived from easily accessible, cost-effective and non-invasive assessment to accurately detect SCD patients who will progress to AD dementia. METHODS: We will include patients who self-referred to our memory clinic and are diagnosed with SCD. Participants will undergo: clinical, neurologic and neuropsychological examination, estimation of cognitive reserve and depression, evaluation of personality traits, APOE and BDNF genotyping, electroencephalography and event-related potential recording, lumbar puncture for measurement of Aß42, t-tau, and p-tau concentration and Aß42/Aß40 ratio. Recruited patients will have follow-up neuropsychological examinations every two years. Collected data will be used to train a machine learning algorithm to define the risk of being carriers of AD and progress to dementia in patients with SCD. DISCUSSION: This is the first study to investigate the application of machine learning to predict AD in patients with SCD. Since all the features we will consider can be derived from non-invasive and easily accessible assessments, our expected results may provide evidence for defining cost-effective and globally scalable tools to estimate the risk of AD and address the needs of patients with memory complaints. In the era of DMTs, this will have crucial implications for the early identification of patients suitable for treatment in the initial stages of AD. TRIAL REGISTRATION NUMBER (TRN): NCT05569083.

Intelligibility of speech in Parkinson's disease relies on anatomically segregated subthalamic beta oscillations.

BACKGROUND: Speech impairment is commonly reported in Parkinson's disease and is not consistently improved by available therapies - including deep brain stimulation of the subthalamic nucleus (STN-DBS), which can worsen communication performance in some patients. Improving the outcome of STN-DBS on speech is difficult due to our incomplete understanding of the contribution of the STN to fluent speaking. OBJECTIVE: To assess the relationship between subthalamic neural activity and speech production and intelligibility. METHODS: We investigated bilateral STN local field potentials (LFPs) in nine parkinsonian patients chronically implanted with DBS during overt reading. LFP spectral features were correlated with clinical scores and measures of speech intelligibility. RESULTS: Overt reading was associated with increased beta-low ([1220) Hz) power in the left STN, whereas speech intelligibility correlated positively with beta-high ([2030) Hz) power in the right STN. CONCLUSION: We identified separate contributions from frequency and brain lateralization of the STN in the execution of an overt reading motor task and its intelligibility. This subcortical organization could be exploited for new adaptive stimulation strategies capable of identifying the occurrence of speaking behavior and facilitating its functional execution.

Predicting party switching through machine learning and open data.

Parliament dynamics might seem erratic at times. Predicting future voting patterns could support policy design based on the simulation of voting scenarios. The availability of open data on legislative activities and machine learning tools might enable such prediction. In our paper, we provide evidence for this statement by developing an algorithm able to predict party switching in the Italian Parliament with over 70% accuracy up to two months in advance. The analysis was based on voting data from the XVII (2013-2018) and XVIII (2018-2022) Italian legislature. We found party switchers exhibited higher participation in secret ballots and showed a progressive decrease in coherence with their party's majority votes up to two months before the actual switch. These results show how machine learning combined with political open data can support predicting and understanding political dynamics.

Fast-Spiking Interneurons of the Premotor Cortex Contribute to Initiation and Execution of Spontaneous Actions.

Planning and execution of voluntary movement depend on the contribution of distinct classes of neurons in primary motor and premotor areas. However, timing and pattern of activation of GABAergic cells during specific motor behaviors remain only partly understood. Here, we directly compared the response properties of putative pyramidal neurons (PNs) and GABAergic fast-spiking neurons (FSNs) during spontaneous licking and forelimb movements in male mice. Recordings centered on the face/mouth motor field of the anterolateral motor cortex (ALM) revealed that FSNs fire longer than PNs and earlier for licking, but not for forelimb movements. Computational analysis revealed that FSNs carry vastly more information than PNs about the onset of movement. While PNs differently modulate their discharge during distinct motor acts, most FSNs respond with a stereotyped increase in firing rate. Accordingly, the informational redundancy was greater among FSNs than PNs. Finally, optogenetic silencing of a subset of FSNs reduced spontaneous licking movement. These data suggest that a global rise of inhibition contributes to the initiation and execution of spontaneous motor actions.SIGNIFICANCE STATEMENT Our study contributes to clarifying the causal role of fast-spiking neurons (FSNs) in driving initiation and execution of specific, spontaneous movements. Within the face/mouth motor field of mice premotor cortex, FSNs fire before pyramidal neurons (PNs) with a specific activation pattern: they reach their peak of activity earlier than PNs during the initiation of licking, but not of forelimb, movements; duration of FSNs activity is also greater and exhibits less selectivity for the movement type, as compared with that of PNs. Accordingly, FSNs appear to carry more redundant information than PNs. Optogenetic silencing of FSNs reduced spontaneous licking movement, suggesting that FSNs contribute to the initiation and execution of specific spontaneous movements, possibly by sculpting response selectivity of nearby PNs.

Uneven Terrain Recognition Using Neuromorphic Haptic Feedback.

Recent years have witnessed relevant advancements in the quality of life of persons with lower limb amputations thanks to the technological developments in prosthetics. However, prostheses that provide information about the foot-ground interaction, and in particular about terrain irregularities, are still missing on the market. The lack of tactile feedback from the foot sole might lead subjects to step on uneven terrains, causing an increase in the risk of falling. To address this issue, a biomimetic vibrotactile feedback system that conveys information about gait and terrain features sensed by a dedicated insole has been assessed with intact subjects. After having shortly experienced both even and uneven terrains, the recruited subjects discriminated them with an accuracy of 87.5%, solely relying on the replay of the vibrotactile feedback. With the objective of exploring the human decoding mechanism of the feedback startegy, a KNN classifier was trained to recognize the uneven terrains. The outcome suggested that the subjects achieved such performance with a temporal dynamics of 45 ms. This work is a leap forward to assist lower-limb amputees to appreciate the floor conditions while walking, adapt their gait and promote a more confident use of their artificial limb.

Young children can use their subjective straight-ahead to remap visuo-motor alterations.

Young children and adults process spatial information differently: the former use their bodies as primary reference, while adults seem capable of using abstract frames. The transition is estimated to occur between the 6th and the 12th year of age. The mechanisms underlying spatial encoding in children and adults are unclear, as well as those underlying the transition. Here, we investigated the role of the subjective straight-ahead (SSA), the body antero-posterior half-plane mental model, in spatial encoding before and after the expected transition. We tested 6-7-year-old and 10-11-year-old children, and adults on a spatial alignment task in virtual reality, searching for differences in performance when targets were placed frontally or sideways. The performance differences were assessed both in a naturalistic baseline condition and in a test condition that discouraged using body-centered coordinates through a head-related visuo-motor conflict. We found no differences in the baseline condition, while all groups showed differences between central and lateral targets (SSA effect) in the visuo-motor conflict condition, and 6-7-year-old children showed the largest effect. These results confirm the expected transition timing; moreover, they suggest that children can abstract from the body using their SSA and that the transition underlies the maturation of a world-centered reference frame.

Degradation of EEG microstates patterns in subjective cognitive decline and mild cognitive impairment: Early biomarkers along the Alzheimer's Disease continuum?

Alzheimer's disease (AD) pathological changes may begin up to decades earlier than the appearance of the first symptoms of cognitive decline. Subjective cognitive decline (SCD) could be the first pre-clinical sign of possible AD, which might be followed by mild cognitive impairment (MCI), the initial stage of clinical cognitive decline. However, the neural correlates of these prodromic stages are not completely clear yet. Recent studies suggest that EEG analysis tools characterizing the cortical activity as a whole, such as microstates and cortical regions connectivity, might support a characterization of SCD and MCI conditions. Here we test this approach by performing a broad set of analyses to identify the prominent EEG markers differentiating SCD (n = 57), MCI (n = 46) and healthy control subjects (HC, n = 19). We found that the salient differences were in the temporal structure of the microstates patterns, with MCI being associated with less complex sequences due to the altered transition probability, frequency and duration of canonic microstate C. Spectral content of EEG, network connectivity, and spatial arrangement of microstates were instead largely similar in the three groups. Interestingly, comparing properties of EEG microstates in different cerebrospinal fluid (CSF) biomarkers profiles, we found that canonic microstate C displayed significant differences in topography in AD-like profile. These results show that the progression of dementia might be associated with a degradation of the cortical organization captured by microstates analysis, and that this leads to altered transitions between cortical states. Overall, our approach paves the way for the use of non-invasive EEG recordings in the identification of possible biomarkers of progression to AD from its prodromal states.

Dopamine depletion leads to pathological synchronization of distinct basal ganglia loops in the beta band.

Motor symptoms of Parkinson's Disease (PD) are associated with dopamine deficits and pathological oscillation of basal ganglia (BG) neurons in the ß range ([12-30] Hz). However, how dopamine depletion affects the oscillation dynamics of BG nuclei is still unclear. With a spiking neurons model, we here capture the features of BG nuclei interactions leading to oscillations in dopamine-depleted condition. We highlight that both the loop between subthalamic nucleus (STN) and Globus Pallidus pars externa (GPe) and the loop between striatal fast spiking and medium spiny neurons and GPe display resonances in the ß range, and synchronize to a common ß frequency through interaction. Crucially, the synchronization depends on dopamine depletion: the two loops are largely independent for high levels of dopamine, but progressively synchronize as dopamine is depleted due to the increased strength of the striatal loop. The model is validated against recent experimental reports on the role of cortical inputs, STN and GPe activity in the generation of ß oscillations. Our results highlight the role of the interplay between the GPe-STN and the GPe-striatum loop in generating sustained ß oscillations in PD subjects, and explain how this interplay depends on the level of dopamine. This paves the way to the design of therapies specifically addressing the onset of pathological ß oscillations.