Altered spreading of fast aperiodic brain waves relates to disease duration in Amyotrophic Lateral Sclerosis.

OBJECTIVE: To test the hypothesis that patients affected by Amyotrophic Lateral Sclerosis (ALS) show an altered spatio-temporal spreading of neuronal avalanches in the brain, and that this may related to the clinical picture. METHODS: We obtained the source-reconstructed magnetoencephalography (MEG) signals from thirty-six ALS patients and forty-two healthy controls. Then, we used the construct of the avalanche transition matrix (ATM) and the corresponding network parameter nodal strength to quantify the changes in each region, since this parameter provides key information about which brain regions are mostly involved in the spreading avalanches. RESULTS: ALS patients presented higher values of the nodal strength in both cortical and sub-cortical brain areas. This parameter correlated directly with disease duration. CONCLUSIONS: In this work, we provide a deeper characterization of neuronal avalanches propagation in ALS, describing their spatio-temporal trajectories and identifying the brain regions most likely to be involved in the process. This makes it possible to recognize the brain areas that take part in the pathogenic mechanisms of ALS. Furthermore, the nodal strength of the involved regions correlates directly with disease duration. SIGNIFICANCE: Our results corroborate the clinical relevance of aperiodic, fast large-scale brain activity as a biomarker of microscopic changes induced by neurophysiological processes.

The Effect of Sleep Deprivation on Brain Fingerprint Stability: A Magnetoencephalography Validation Study.

This study examined the stability of the functional connectome (FC) over time using fingerprint analysis in healthy subjects. Additionally, it investigated how a specific stressor, namely sleep deprivation, affects individuals' differentiation. To this aim, 23 healthy young adults underwent magnetoencephalography (MEG) recording at three equally spaced time points within 24 h: 9 a.m., 9 p.m., and 9 a.m. of the following day after a night of sleep deprivation. The findings indicate that the differentiation was stable from morning to evening in all frequency bands, except in the delta band. However, after a night of sleep deprivation, the stability of the FCs was reduced. Consistent with this observation, the reduced differentiation following sleep deprivation was found to be negatively correlated with the effort perceived by participants in completing the cognitive task during sleep deprivation. This correlation suggests that individuals with less stable connectomes following sleep deprivation experienced greater difficulty in performing cognitive tasks, reflecting increased effort.

Flexibility of brain dynamics is increased and predicts clinical impairment in relapsing-remitting but not in secondary progressive multiple sclerosis.

Large-scale brain activity has long been investigated under the erroneous assumption of stationarity. Nowadays, we know that resting-state functional connectivity is characterized by aperiodic, scale-free bursts of activity (i.e. neuronal avalanches) that intermittently recruit different brain regions. These different patterns of activity represent a measure of brain flexibility, whose reduction has been found to predict clinical impairment in multiple neurodegenerative diseases such as Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease. Brain flexibility has been recently found increased in multiple sclerosis, but its relationship with clinical disability remains elusive. Also, potential differences in brain dynamics according to the multiple sclerosis clinical phenotypes remain unexplored so far. We performed a brain dynamics study quantifying brain flexibility utilizing the 'functional repertoire' (i.e. the number of configurations of active brain areas) through source reconstruction of magnetoencephalography signals in a cohort of 25 multiple sclerosis patients (10 relapsing-remitting multiple sclerosis and 15 secondary progressive multiple sclerosis) and 25 healthy controls. Multiple sclerosis patients showed a greater number of unique reconfigurations at fast time scales as compared with healthy controls. This difference was mainly driven by the relapsing-remitting multiple sclerosis phenotype, whereas no significant differences in brain dynamics were found between secondary progressive multiple sclerosis and healthy controls. Brain flexibility also showed a different predictive power on clinical disability according to the multiple sclerosis type. For the first time, we investigated brain dynamics in multiple sclerosis patients through high temporal resolution techniques, unveiling differences in brain flexibility according to the multiple sclerosis phenotype and its relationship with clinical disability.

The effect of dopaminergic treatment on whole body kinematics explored through network theory.

Three-dimensional motion analysis represents a quantitative approach to assess spatio-temporal and kinematic changes in health and disease. However, these parameters provide only segmental information, discarding minor changes of complex whole body kinematics characterizing physiological and/or pathological conditions. We aimed to assess how levodopa intake affects the whole body, analyzing the kinematic interactions during gait in Parkinson's disease (PD) through network theory which assess the relationships between elements of a system. To this end, we analysed gait data of 23 people with PD applying network theory to the acceleration kinematic data of 21 markers placed on participants' body landmarks. We obtained a matrix of kinematic interactions (i.e., the kinectome) for each participant, before and after the levodopa intake, we performed a topological analysis to evaluate the large-scale interactions among body elements, and a multilinear regression analysis to verify whether the kinectome's topology could predict the clinical variations induced by levodopa. We found that, following levodopa intake, patients with PD showed less trunk and head synchronization (p-head = 0.048; p-7th cervical vertebrae = 0.032; p-10th thoracic vertebrae = 0.006) and an improved upper-lower limbs synchronization (elbows right, p = 0.002; left, p = 0.005), (wrists right, p = 0.003; left, p = 0.002; knees right, p = 0.003; left, p = 0.039) proportional to the UPDRS-III scores. These results may be attributable to the reduction of rigidity, following pharmacological treatment.

Brain flexibility increases during the peri-ovulatory phase as compared to early follicular phase of the menstrual cycle.

The brain operates in a flexible dynamic regime, generating complex patterns of activity (i.e. neuronal avalanches). This study aimed at describing how brain dynamics change according to menstrual cycle (MC) phases. Brain activation patterns were estimated from resting-state magnetoencephalography (MEG) scans, acquired from women at early follicular (T1), peri-ovulatory (T2) and mid-luteal (T3) phases of the MC. We investigated the functional repertoire (number of brain configurations based on fast high-amplitude bursts of the brain signals) and the region-specific influence on large-scale dynamics across the MC. Finally, we assessed the relationship between sex hormones and changes in brain dynamics. A significantly larger number of visited configurations in T2 as compared to T1 was specifically observed in the beta frequency band. No relationship between changes in brain dynamics and sex hormones was evident. Finally, we showed that the left posterior cingulate gyrus and the right insula were recruited more often in the functional repertoire during T2 as compared to T1, while the right pallidum was more often part of the functional repertoires during T1 as compared to T2. In summary, we showed hormone-independent increased flexibility of the brain dynamics during the ovulatory phase. Moreover, we demonstrated that several specific brain regions play a key role in determining this change.

Topological changes of fast large-scale brain dynamics in mild cognitive impairment predict early memory impairment: a resting-state, source reconstructed, magnetoencephalography study.

Functional connectivity has been used as a framework to investigate widespread brain interactions underlying cognitive deficits in mild cognitive impairment (MCI). However, many functional connectivity metrics focus on the average of the periodic activities, disregarding the aperiodic bursts of activity (i.e., the neuronal avalanches) characterizing the large-scale dynamic activities of the brain. Here, we apply the recently described avalanche transition matrix framework to source-reconstructed magnetoencephalography signals in a cohort of 32 MCI patients and 32 healthy controls to describe the spatio-temporal features of neuronal avalanches and explore their topological properties. Our results showed that MCI patients showed a more centralized network (as assessed by higher values of the degree divergence and leaf fraction) as compared to healthy controls. Furthermore, we found that the degree divergence (in the theta band) was predictive of hippocampal memory impairment. These findings highlight the role of the changes of aperiodic bursts in clinical conditions and may contribute to a more thorough phenotypical assessment of patients.

Reduced clinical connectome fingerprinting in multiple sclerosis predicts fatigue severity.

BACKGROUND: Brain connectome fingerprinting is progressively gaining ground in the field of brain network analysis. It represents a valid approach in assessing the subject-specific connectivity and, according to recent studies, in predicting clinical impairment in some neurodegenerative diseases. Nevertheless, its performance, and clinical utility, in the Multiple Sclerosis (MS) field has not yet been investigated. METHODS: We conducted the Clinical Connectome Fingerprint (CCF) analysis on source-reconstructed magnetoencephalography signals in a cohort of 50 subjects: twenty-five MS patients and twenty-five healthy controls. RESULTS: All the parameters of identifiability, in the alpha band, were reduced in patients as compared to controls. These results implied a lower similarity between functional connectomes (FCs) of the same patient and a reduced homogeneity among FCs in the MS group. We also demonstrated that in MS patients, reduced identifiability was able to predict, fatigue level (assessed by the Fatigue Severity Scale). CONCLUSION: These results confirm the clinical usefulness of the CCF in both identifying MS patients and predicting clinical impairment. We hope that the present study provides future prospects for treatment personalization on the basis of individual brain connectome.

The Effects of Vibratory and Acoustic Stimulations on Postural Control in Healthy People: A Systematic Review.

Research on human posture and balance control has grown in recent years, leading to continued advances in their understanding. The ability to maintain balance is attributed to the interplay of the visual, vestibular, and somatosensory systems, although an important role is also played by the auditory system. The lack or deficit in any of these systems leads to a reduced stability that may be counterbalanced by the integration of all the remaining sensory information. Auditory and vibratory stimulation have been found to be useful to enhance balance alongside daily activities either in healthy or pathological subjects; nevertheless, while widely investigated, the literature relating to these approaches is still fragmented. This review aims at addressing this by collecting, organising, and discussing all the literature to date on the effects of the various acoustic and vibratory stimulation techniques available on static upright posture in healthy subjects. In addition, this review intends to provide a solid and comprehensive starting point for all the researchers interested in these research areas. A systematic search of the literature was performed and a total of 33 articles (24 on vibratory stimulation and 9 on acoustic stimulation) were included in our analysis. For all articles, several elements were highlighted including: the study sample, the characteristics of the stimulations, the recording instruments, the experimental protocols, and outcomes. Overall, both stimulations analysed were found to have a positive effect on balance but more research is needed to align those alternative approaches to the traditional ones.

Fading of brain network fingerprint in Parkinson's disease predicts motor clinical impairment.

The clinical connectome fingerprint (CCF) was recently introduced as a way to assess brain dynamics. It is an approach able to recognize individuals, based on the brain network. It showed its applicability providing network features used to predict the cognitive decline in preclinical Alzheimer's disease. In this article, we explore the performance of CCF in 47 Parkinson's disease (PD) patients and 47 healthy controls, under the hypothesis that patients would show reduced identifiability as compared to controls, and that such reduction could be used to predict motor impairment. We used source-reconstructed magnetoencephalography signals to build two functional connectomes for 47 patients with PD and 47 healthy controls. Then, exploiting the two connectomes per individual, we investigated the identifiability characteristics of each subject in each group. We observed reduced identifiability in patients compared to healthy individuals in the beta band. Furthermore, we found that the reduction in identifiability was proportional to the motor impairment, assessed through the Unified Parkinson's Disease Rating Scale, and, interestingly, able to predict it (at the subject level), through a cross-validated regression model. Along with previous evidence, this article shows that CCF captures disrupted dynamics in neurodegenerative diseases and is particularly effective in predicting motor clinical impairment in PD.

Flexibility of Fast Brain Dynamics and Disease Severity in Amyotrophic Lateral Sclerosis.

BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a multisystem disorder, as supported by clinical, molecular, and neuroimaging evidence. As a consequence, predicting clinical features requires a description of large-scale neuronal dynamics. Normally, brain activity dynamically reconfigures over time, recruiting different brain areas. Brain pathologies induce stereotyped dynamics which, in turn, are linked to clinical impairment. Hence, based on recent evidence showing that brain functional networks become hyperconnected as ALS progresses, we hypothesized that the loss of flexible dynamics in ALS would predict the symptoms severity. METHODS: To test this hypothesis, we quantified flexibility using the "functional repertoire" (i.e., the number of configurations of active brain areas) as measured from source-reconstructed magnetoencephalography (MEG) in patients with ALS and healthy controls. The activity of brain areas was reconstructed in the classic frequency bands, and the functional repertoire was estimated to quantify spatiotemporal fluctuations of brain activity. Finally, we built a k-fold cross-validated multilinear model to predict the individual clinical impairment from the size of the functional repertoire. RESULTS: Comparing 42 patients with ALS and 42 healthy controls, we found a more stereotyped brain dynamics in patients with ALS (p < 0.05), as conveyed by the smaller functional repertoire. The relationship between the size of the functional repertoire and the clinical scores in the ALS group showed significant correlations in both the delta and the theta frequency bands. Furthermore, through a k-fold cross-validated multilinear regression model, we found that the functional repertoire predicted both clinical staging (p < 0.001 and p < 0.01, in the delta and theta bands, respectively) and symptoms severity (p < 0.001, in both the delta and theta bands). DISCUSSION: Our work shows that (1) ALS pathology reduces the flexibility of large-scale brain dynamics, (2) subcortical regions play a key role in determining brain dynamics, and (3) reduced brain flexibility predicts disease stage and symptoms severity. Our approach provides a noninvasive tool to quantify alterations in brain dynamics in ALS (and, possibly, other neurodegenerative diseases), thus opening new opportunities in disease management and a framework to test, in the near future, the effects of disease-modifying interventions at the whole-brain level.

Topological changes of brain network during mindfulness meditation: an exploratory source level magnetoencephalographic study.

We have previously evidenced that Mindfulness Meditation (MM) in experienced meditators (EMs) is associated with long-lasting topological changes in resting state condition. However, what occurs during the meditative phase is still debated. Utilizing magnetoencephalography (MEG), the present study is aimed at comparing the topological features of the brain network in a group of EMs (n = 26) during the meditative phase with those of individuals who had no previous experience of any type of meditation (NM group, n = 29). A wide range of topological changes in the EM group as compared to the NM group has been shown. Specifically, in EMs, we have observed increased betweenness centrality in delta, alpha, and beta bands in both cortical (left medial orbital cortex, left postcentral area, and right visual primary cortex) and subcortical (left caudate nucleus and thalamus) areas. Furthermore, the degree of beta band in parietal and occipital areas of EMs was increased too. Our exploratory study suggests that the MM can change the functional brain network and provides an explanatory hypothesis on the brain circuits characterizing the meditative process.

The kinectome: A comprehensive kinematic map of human motion in health and disease.

Human voluntary movement stems from the coordinated activations in space and time of many musculoskeletal segments. However, the current methodological approaches to study human movement are still limited to the evaluation of the synergies among a few body elements. Network science can be a useful approach to describe movement as a whole and to extract features that are relevant to understanding both its complex physiology and the pathophysiology of movement disorders. Here, we propose to represent human movement as a network (that we named the kinectome), where nodes represent body points, and edges are defined as the correlations of the accelerations between each pair of them. We applied this framework to healthy individuals and patients with Parkinson's disease, observing that the patients' kinectomes display less symmetrical patterns as compared to healthy controls. Furthermore, we used the kinectomes to successfully identify both healthy and diseased subjects using short gait recordings. Finally, we highlighted topological features that predict the individual clinical impairment in patients. Our results define a novel approach to study human movement. While deceptively simple, this approach is well-grounded, and represents a powerful tool that may be applied to a wide spectrum of frameworks.

The progressive loss of brain network fingerprints in Amyotrophic Lateral Sclerosis predicts clinical impairment.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by functional connectivity alterations in both motor and extra-motor brain regions. Within the framework of network analysis, fingerprinting represents a reliable approach to assess subject-specific connectivity features within a given population (healthy or diseased). Here, we applied the Clinical Connectome Fingerprint (CCF) analysis to source-reconstructed magnetoencephalography (MEG) signals in a cohort of seventy-eight subjects: thirty-nine ALS patients and thirty-nine healthy controls. We set out to develop an identifiability matrix to assess the extent to which each patient was recognisable based on his/her connectome, as compared to healthy controls. The analysis was performed in the five canonical frequency bands. Then, we built a multilinear regression model to test the ability of the "clinical fingerprint" to predict the clinical evolution of the disease, as assessed by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-r), the King's disease staging system, and the Milano-Torino Staging (MiToS) disease staging system. We found a drop in the identifiability of patients in the alpha band compared to the healthy controls. Furthermore, the "clinical fingerprint" was predictive of the ALSFRS-r (p = 0.0397; ß = 32.8), the King's (p = 0.0001; ß = -7.40), and the MiToS (p = 0.0025; ß = -4.9) scores. Accordingly, it negatively correlated with the King's (Spearman's rho = -0.6041, p = 0.0003) and MiToS scales (Spearman's rho = -0.4953, p = 0.0040). Our results demonstrated the ability of the CCF approach to predict the individual motor impairment in patients affected by ALS. Given the subject-specificity of our approach, we hope to further exploit it to improve disease management.

Sensitivity to gait improvement after levodopa intake in Parkinson's disease: A comparison study among synthetic kinematic indices.

The synthetic indices are widely used to describe balance and stability during gait. Some of these are employed to describe the gait features in Parkinson's disease (PD). However, the results are sometimes inconsistent, and the same indices are rarely used to compare the individuals affected by PD before and after levodopa intake (OFF and ON condition, respectively). Our aim was to investigate which synthetic measure among Harmonic Ratio, Jerk Ratio, Golden Ratio and Trunk Displacement Index is representative of gait stability and harmony, and which of these are more sensitive to the variations between OFF and ON condition. We found that all indices, except the Jerk Ratio, significantly improve after levodopa. Only the improvement of the Trunk Displacement Index showed a direct correlation with the motor improvement measured through the clinical scale UPDRS-III (Unified Parkinson's Disease Rating Scale-part III). In conclusion, we suggest that the synthetic indices can be useful to detect motor changes induced by, but not all of them clearly correlate with the clinical changes achieved with the levodopa administration. In our analysis, only the Trunk Displacement Index was able to show a clear relationship with the PD clinical motor improvement.

A night of sleep deprivation alters brain connectivity and affects specific executive functions.

Sleep is a fundamental physiological process necessary for efficient cognitive functioning especially in relation to memory consolidation and executive functions, such as attentional and switching abilities. The lack of sleep strongly alters the connectivity of some resting-state networks, such as default mode network and attentional network. In this study, by means of magnetoencephalography (MEG) and specific cognitive tasks, we investigated how brain topology and cognitive functioning are affected by 24 h of sleep deprivation (SD). Thirty-two young men underwent resting-state MEG recording and evaluated in letter cancellation task (LCT) and task switching (TS) before and after SD. Results showed a worsening in the accuracy and speed of execution in the LCT and a reduction of reaction times in the TS, evidencing thus a worsening of attentional but not of switching abilities. Moreover, we observed that 24 h of SD induced large-scale rearrangements in the functional network. These findings evidence that 24 h of SD is able to alter brain connectivity and selectively affects cognitive domains which are under the control of different brain networks.

The effects of different frequencies of rhythmic acoustic stimulation on gait stability in healthy elderly individuals: a pilot study.

The efficacy of rhythmic acoustic stimulation (RAS) to improve gait and balance in healthy elderly individuals is controversial. Our aim was to investigate, through 3D gait analysis, the effect of different types of RAS (fixed frequency and based on subject-specific cadence), using conventional gait parameters and the trunk displacement as readouts. Walking at a fixed frequency of 80 bpm, the subjects showed extended duration of gait cycle and increased gait variability while the same individuals, walking at a fixed frequency of 120 bpm, showed reduced trunk sway and gait cycle duration. With regard to the RAS at subject-specific frequencies, walking at 90% of the subject-specific average cadence did not significantly modify the gait parameters, except for the speed, which was reduced. In contrast, walking at 100% and 110% of the mean cadence caused increased stride length and a slight reduction of temporal parameters and trunk sway. In conclusion, this pilot study shows that using RAS at fixed frequencies might be an inappropriate strategy, as it is not adjusted to individual gait characteristics. On the other hand, RAS frequencies equal to or slightly higher than each subject's natural cadence seem to be beneficial for gait and stability.

Functional brain network topology across the menstrual cycle is estradiol dependent and correlates with individual well-being.

The menstrual cycle (MC) is a sex hormone-related phenomenon that repeats itself cyclically during the woman's reproductive life. In this explorative study, we hypothesized that coordinated variations of multiple sex hormones may affect the large-scale organization of the brain functional network and that, in turn, such changes might have psychological correlates, even in the absence of overt clinical signs of anxiety and/or depression. To test our hypothesis, we investigated longitudinally, across the MC, the relationship between the sex hormones and both brain network and psychological changes. We enrolled 24 naturally cycling women and, at the early-follicular, peri-ovulatory, and mid-luteal phases of the MC, we performed: (a) sex hormone dosage, (b) magnetoencephalography recording to study the brain network topology, and (c) psychological questionnaires to quantify anxiety, depression, self-esteem, and well-being. We showed that during the peri-ovulatory phase, in the alpha band, the leaf fraction and the tree hierarchy of the brain network were reduced, while the betweenness centrality (BC) of the right posterior cingulate gyrus (rPCG) was increased. Furthermore, the increase in BC was predicted by estradiol levels. Moreover, during the luteal phase, the variation of estradiol correlated positively with the variations of both the topological change and environmental mastery dimension of the well-being test, which, in turn, was related to the increase in the BC of rPCG. Our results highlight the effects of sex hormones on the large-scale brain network organization as well as on their possible relationship with the psychological state across the MC. Moreover, the fact that physiological changes in the brain topology occur throughout the MC has widespread implications for neuroimaging studies.

A synthetic kinematic index of trunk displacement conveying the overall motor condition in Parkinson's disease.

Parkinson's disease (PD) is characterized by motor impairment, affecting quality of life and increasing fall risk, due to ineffective postural control. To this day, the diagnosis remains based on clinical approach. Similarly, motor evaluation is based on heterogeneous, operator-dependent observational criteria. A synthetic, replicable index to quantify motor impairment is still lacking. Hence, we have designed a new measure of postural stability which assesses the trunk displacement in relation to the center of mass, that we named trunk displacement index (TDI). Twenty-three PD patients and twenty-three healthy controls underwent motor examination through a stereophotogrammetric system. A correlation analysis was performed to assess the relationship of TDI with gait parameters and clinical motor scale (UPDRS-III). The TDI sensitivity was estimated, comparing pre- and post- L-DOPA subclinical dose intake. The TDI showed significant correlations with many gait parameters and with the UPDRS-III. Furthermore, the TDI resulted capable in discriminating between off and on state in PD, whereas gait parameters failed two show any difference between those two conditions. Our results suggest that the TDI may be considered a highly sensitive biomechanical index, reflecting the overall motor condition in PD, and provided of clinical relevance due to the correlation with the clinical evaluation.

In Amyotrophic Lateral Sclerosis Blood Cytokines Are Altered, but Do Not Correlate with Changes in Brain Topology.

Aim: The present study aims at investigating the possible correlation between peripheral markers of inflammation and brain networks. Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease dominated by progressive motor impairment. Among the complex mechanisms contributing to the pathogenesis of the disease, neuroinflammation, which is associated with altered circulating cytokine levels, is suggested to play a prominent role. Methods: Based on magnetoencephalography data, we estimated topological properties of the brain networks in ALS patients and healthy controls. Subsequently, the blood levels of a subset of cytokines were assayed. Finally, we modeled the brain topological features in the function of the cytokine levels. Results: Significant differences were found in the levels of the cytokines interleukin (IL)-4, IL-1ß, and interferon-gamma (IFN-γ) between patients and controls. In particular, IL-4 and IL-1ß levels increased in ALS patients, while the IFN-γ level was higher in healthy controls. We also detected modifications in brain global topological parameters in terms of hyperconnectedness. Despite both blood cytokines and brain topology being altered in ALS patients, such changes do not appear to be in a direct relationship. Conclusion: Our results would be in line with the idea that topological changes relate to neurodegenerative processes. However, the absence of correlation between blood cytokines and topological parameters of brain networks does not preclude that inflammatory processes contribute to the alterations of the brain networks. Impact statement The progression of amyotrophic lateral sclerosis entails both neurodegenerative and inflammatory processes. Furthermore, disease progression induces global modifications of the brain networks, with advanced stages showing a more compact, hyperconnected network topology. The pathophysiological processes underlying topological changes are unknown. In this article, we hypothesized that the global inflammatory profile would relate to the topological alterations. Our results showed that this is not the case, as modeling the topological properties as a function of the inflammatory state did not yield good predictions. Hence, our results suggest that topological changes might directly relate to neurodegenerative processes instead.

Gait abnormalities in minimally disabled people with Multiple Sclerosis: A 3D-motion analysis study.

BACKGROUND: People with Relapsing-Remitting Multiple Sclerosis (pwRR-MS), may be affected by subclinical gait impairment. The Expanded Disability Status Scale, the most used scale to assess MS related disability, may be insensitive to subclinical gait disability. Minor gait abnormalities may be detected by three Dimensional-Gait Analysis (3D-GA). OBJECTIVES: To investigate gait pattern in minimally disabled pwRR-MS by 3D-GA during walking (single task, SinT), and cognitive dual tasks (CogDT) and to evaluate correlations between altered gait parameters, cognitive scores, lesion load (LL) and brain atrophy measures. METHODS: Twenty-two pwRR-MS and twenty-one healthy controls (HCs), underwent neuropsychological (NP) evaluation, and brain MRI to assess brain volumes and lesion load (only in pwRR-MS) and 3D-GA. RESULTS: Both pwRR-MS and HCs were considered cognitively preserved (CP). During SinT pwRR-MS, compared to HCs, showed an impairment of velocity (increase of cycle time), stability (increase of stance time, swing time and coefficients of variability (CV) of swing time) and kinematic (increase of ankle dorsiflexion) parameters. During CogDT, the changes of velocity and stability parameters observed in SinT were confirmed. Moreover, a statistically significant increase of the double limb support was observed. Regarding the kinematic parameters, during CogDT, an increase of ankle dorsiflexion during mid and terminal stance phases of gait cycle was observed. No significant correlations were found between gait abnormalities and cognitive status or MRI structural damage in both groups. CONCLUSIONS: The subclinical abnormal gait in asymptomatic and CP pwRR-MS, may be detected by 3D-GA.