Federica Bertolucci

Neuroplastic Changes Following Brain Ischemia and their Contribution to Stroke Recovery: Novel Approaches in Neurorehabilitation

Ischemic damage to the brain triggers substantial reorganization of spared areas and pathways, which is associated with limited, spontaneous restoration of function. A better understanding of this plastic remodeling is crucial to develop more effective strategies for stroke rehabilitation. In this review article, we discuss advances in the comprehension of post-stroke network reorganization in patients and animal models. We first focus on rodent studies that have shed light on the mechanisms underlying neuronal remodeling in the perilesional area and contralesional hemisphere after motor cortex infarcts. Analysis of electrophysiological data has demonstrated brain-wide alterations in functional connectivity in both hemispheres, well beyond the infarcted area. We then illustrate the potential use of non-invasive brain stimulation (NIBS) techniques to boost recovery. We finally discuss rehabilitative protocols based on robotic devices as a tool to promote endogenous plasticity and functional restoration.

Unidirectional brain to muscle connectivity reveals motor cortex control of leg muscles during stereotyped walking

Abstract In lower mammals, locomotion seems to be mainly regulated by subcortical and spinal networks. On the contrary, recent evidence suggests that in humans the motor cortex is also significantly engaged during complex locomotion tasks. However, a detailed understanding of cortical contribution to locomotion is still lacking especially during stereotyped activities. Here, we show that cortical motor areas finely control leg muscle activation during treadmill stereotyped walking. Using a novel technique based on a combination of Reliable Independent Component Analysis, source localization and effective connectivity, and by combining electroencephalographic (EEG) and electromyographic (EMG) recordings in able‐bodied adults we were able to examine for the first time cortical activation patterns and cortico‐muscular connectivity including information flow direction. Results not only provided evidence of cortical activity associated with locomotion, but demonstrated significant causal unidirectional drive from contralateral motor cortex to muscles in the swing leg. These insights overturn the traditional view that human cortex has a limited role in the control of stereotyped locomotion, and suggest useful hypotheses concerning mechanisms underlying gait under other conditions. One sentence summary Motor cortex proactively drives contralateral swing leg muscles during treadmill walking, counter to the traditional view of stereotyped human locomotion. HighlightsCortical contributions to stereotyped locomotion are still not well understood.We studied EEG – EMG effective cortico‐muscular connectivity during treadmill walking.A novel technique based on reliable source localization and effective connectivity is proposed.The Motor Cortex drives leg muscles even during stereotyped locomotion.The results counter the traditional view of limited Cortex involvement in stereotyped locomotion.

Using Brain Oscillations and Corticospinal Excitability to Understand and Predict Post-Stroke Motor Function

What determines motor recovery in stroke is still unknown and finding markers that could predict and improve stroke recovery is a challenge. In this study, we aimed at understanding the neural mechanisms of motor function recovery after stroke using neurophysiological markers by means of cortical excitability (transcranial magnetic stimulation—TMS) and brain oscillations (electroencephalography—EEG). In this cross-sectional study, 55 subjects with chronic stroke (62 ± 14 yo, 17 women, 32 ± 42 months post-stroke) were recruited in two sites. We analyzed TMS measures (i.e., motor threshold—MT—of the affected and unaffected sides) and EEG variables (i.e., power spectrum in different frequency bands and different brain regions of the affected and unaffected hemispheres) and their correlation with motor impairment as measured by Fugl-Meyer. Multiple univariate and multivariate linear regression analyses were performed to identify the predictors of good motor function. A significant interaction effect of MT in the affected hemisphere and power in beta bandwidth over the central region for both affected and unaffected hemispheres was found. We identified that motor function positively correlates with beta rhythm over the central region of the unaffected hemisphere, while it negatively correlates with beta rhythm in the affected hemisphere. Our results suggest that cortical activity in the affected and unaffected hemisphere measured by EEG provides new insights on the association between high-frequency rhythms and motor impairment, highlighting the role of an excess of beta in the affected central cortical region in poor motor function in stroke recovery.

Delta Power Is Higher and More Symmetrical in Ischemic Stroke Patients with Cortical Involvement

A brain injury resulting from unilateral stroke critically alters brain functionality and the complex balance within the cortical activity. Such modifications may critically depend on lesion location and cortical involvement. Indeed, recent findings pointed out the necessity of applying a stratification based on lesion location when investigating inter-hemispheric balance in stroke. Here, we tested whether cortical involvement could imply differences in band-specific activity and brain symmetry in post stroke patients with cortico-subcortical and subcortical strokes. We explored brain activity related to lesion location through EEG power analysis and quantitative Electroencephalography (qEEG) measures. Thirty stroke patients in the subacute phase and 10 neurologically intact age-matched right-handed subjects were enrolled. Stroke patients were equally subdivided in two groups based on lesion location: cortico-subcortical (CS, mean age ± SD: 72.21 ± 10.97 years; time since stroke ± SD: 31.14 ± 11.73 days) and subcortical (S, mean age ± SD: 68.92 ± 10.001 years; time since stroke ± SD: 26.93 ± 13.08 days) group. We assessed patients’ neurological status by means of National Institutes of Health Stroke Scale (NIHSS). High density EEG at rest was recorded and power spectral analysis in Delta (1–4 Hz) and Alpha (8–14 Hz) bands was performed. qEEG metrics as pairwise derived Brain Symmetry Index (pdBSI) and Delta/Alpha Ratio (DAR) were computed and correlated with NIHSS score. S showed a lower Delta power in the Unaffected Hemisphere (UH) compared to Affected Hemisphere (AH; z = −1.98, p < 0.05) and a higher Alpha power compared to CS (z = −2.18, p < 0.05). pdBSI was negatively correlated with NIHSS (R = −0.59, p < 0.05). CS showed a higher value and symmetrical distribution of Delta band activity (z = −2.37, p < 0.05), confirmed also by a higher DAR value compared to S (z = −2.48, p < 0.05). Patients with cortico-subcortical and subcortical lesions show different brain symmetry in the subacute phase. Interestingly, in subcortical stroke patient brain activity is related with the clinical function. qEEG measures can be explicative of brain activity related to lesion location and they could allow precise definition of diagnostic-therapeutic algorithms in stroke patients.

Neurophysiological Characterization of Subacute Stroke Patients: A Longitudinal Study

Various degrees of neural reorganization may occur in affected and unaffected hemispheres in the early phase after stroke and several months later. Recent literature suggests to apply a stratification based on lesion location and to consider patients with cortico-subcortical and subcortical strokes separately: different lesion location may also influence therapeutic response. In this study we used a longitudinal approach to perform TMS assessment (Motor Evoked Potentials, MEP, and Silent Period, SP) and clinical evaluations (Barthel Index, Fugl-Meyer Assessment for upper limb motor function and Wolf Motor Function Test) in 10 cortical-subcortical and 10 subcortical ischemic stroke patients. Evaluations were performed in a window between 10 and 45 days (t0) and at 3 months after the acute event (t1). Our main finding is that 3 months after the acute event patients affected by subcortical stroke presented a reduction in contralateral SP duration in the unaffected hemisphere; this trend is related to clinical improvement of upper limb motor function. In conclusion, SP proved to be a valid parameter to characterize cortical reorganization patterns in stroke survivors and provided useful information about motor recovery within 3 months in subcortical patients.

Benefits of an intensive task-oriented circuit training in Multiple Sclerosis patients with mild disability

BACKGROUND Exercise is well tolerated and induces relevant improvements in physical and mental functioning of persons with Multiple Sclerosis (MS). Unfortunately, due to the wide variety of symptoms and the broad range of exercise interventions, it is not possible to make unified exercise recommendation as to what type of exercise is safe and effective for persons with MS. OBJECTIVE The aim was to test the impact of an intensive task-oriented training on motor function and quality of life in 17 MS patients with an Expanded Disability Status Scale (EDSS) between 4 and 5.5. METHODS Patients underwent a two-week intensive, task-oriented rehabilitation program. Outcome measures were: Berg Balance Scale, Gait Dynamic Index, 6 Minute Walking Test, Physiological Cost Index, Fatigue Severity Scale, 10 metres Walking Test, Timed Up and Go test, Short form 36, Multiple Sclerosis Impact Scale, Patient Health Questionnaire. RESULTS All outcome measures showed a significant improvement after the treatment except for the 6 Minute Walking test and the Short form 36 that showed a trend of improvement although not statistically significant. CONCLUSIONS An intensive task-oriented rehabilitation protocol is effective in improving motor function and has a positive impact on quality of life in MS patients with moderate disability.

Clinical Assessments for Predicting Functional Recovery after Stroke

Despite on-going technological developments, clinical assessment remains an essential tool to evaluate the effects of rehabilitation treatment and to predict functional recovery. This paper provides a review of clinical assessment for stroke patients focusing on predictive value of motor, function and participation assessment, taking into consideration some specific evaluations for upper and lower limb function, trunk control, balance and walking. In the future an increased integration between clinical assessment, neurophysiology and neuroimaging will be required, in order to apply specific evaluation pathways to reach a more accurate and customized prognostic stratification.

Simple Tool for Functional and Physiological Stroke Patients Assessment

The assessment of stroke patients is a long lasting process in which physicians estimate the impairment import of the patients through clinical scales and physiological exams. This is a crucial phase for defining the patient treatment as well as monitoring the recovery process. In order to support the whole set of operations involved in the assessment, the authors proposed a simple evaluation tool that easily allows physicians to collect performance, muscles activity and upper-limb kinematic data from patients and thus extract clinically useful information. Preliminary results obtained form 3 healthy subjects and 2 patients demonstrated the suitability of the proposed system for collecting relevant information in just one short session.

Non-invasive brain stimulation for fine motor improvement after stroke: a meta-analysis

The aim of this study was to determine whether non‐invasive brain stimulation (NIBS) techniques improve fine motor performance in stroke. We searched PubMed, EMBASE, Web of Science, SciELO and OpenGrey for randomized clinical trials on NIBS for fine motor performance in stroke patients and healthy participants. We computed Hedges’ g for active and sham groups, pooled data as random‐effects models and performed sensitivity analysis on chronicity, montage, frequency of stimulation and risk of bias. Twenty‐nine studies (351 patients and 152 healthy subjects) were reviewed. Effect sizes in stroke populations for transcranial direct current stimulation and repeated transcranial magnetic stimulation were 0.31 [95% confidence interval (CI), 0.08–0.55; P = 0.010; Tau2, 0.09; I2, 34%; Q, 18.23; P = 0.110] and 0.46 (95% CI, 0.00–0.92; P = 0.05; Tau2, 0.38; I2, 67%; Q, 30.45; P = 0.007). The effect size of non‐dominant healthy hemisphere transcranial direct current stimulation on non‐dominant hand function was 1.25 (95% CI, 0.09–2.41; P = 0.04; Tau2, 1.26; I2, 93%; Q, 40.27; P < 0.001). Our results show that NIBS is associated with gains in fine motor performance in chronic stroke patients and healthy subjects. This supports the effects of NIBS on motor learning and encourages investigation to optimize their effects in clinical and research settings.

Abnormal lactate levels affect motor performance in Myotonic Dystrophy type 1

Myotonic Dystrophy type 1 (DM1) is a dominantly inherited disease comprehending multiple features. Fatigue and exhaustion during exercise often represent significant factors able to negatively influence their compliance to rehabilitation programs. Mitochondrial abnormalities and a significant increase in oxidative markers, previously reported, suggest the hypothesis of a mitochondrial functional impairment. The study aims at evaluating oxidative metabolism efficiency in 18 DM1 patients and in 15 healthy subjects, through analysis of lactate levels at rest and after an incremental exercise test. The exercise protocol consisted of a submaximal incremental exercise performed on an electronically calibrated treadmill, maintained in predominantly aerobic condition. Lactate levels were assessed at rest and at 5, 10 and 30 minutes after the end of the exercise. The results showed early exercise-related fatigue in DM1 patients, as they performed a mean number of 9 steps, while controls completed the whole exercise. Moreover, while resting values of lactate were comparable between the patients and the control group (p=0.69), after the exercise protocol, dystrophic subjects reached higher values of lactate, at any recovery time (p<0,05). These observations suggest an early activation of anaerobic metabolism, thus evidencing an alteration in oxidative metabolism of such dystrophic patients. As far as intense aerobic training could be performed in DM1 patients, in order to improve maximal muscle oxidative capacity and blood lactate removal ability, then, this safe and validate method could be used to evaluate muscle oxidative metabolism and provide an efficient help on rehabilitation programs to be prescribed in such patients.