Giovanni Pellegrino

Modulation of brain plasticity in stroke: a novel model for neurorehabilitation

Noninvasive brain stimulation (NIBS) techniques can be used to monitor and modulate the excitability of intracortical neuronal circuits. Long periods of cortical stimulation can produce lasting effects on brain function, paving the way for therapeutic applications of NIBS in chronic neurological disease. The potential of NIBS in stroke rehabilitation has been of particular interest, because stroke is the main cause of permanent disability in industrial nations, and treatment outcomes often fail to meet the expectations of patients. Despite promising reports from many clinical trials on NIBS for stroke recovery, the number of studies reporting a null effect remains a concern. One possible explanation is that the interhemispheric competition model—which posits that suppressing the excitability of the hemisphere not affected by stroke will enhance recovery by reducing interhemispheric inhibition of the stroke hemisphere, and forms the rationale for many studies—is oversimplified or even incorrect. Here, we critically review the proposed mechanisms of synaptic and functional reorganization after stroke, and suggest a bimodal balance–recovery model that links interhemispheric balancing and functional recovery to the structural reserve spared by the lesion. The proposed model could enable NIBS to be tailored to the needs of individual patients.

Brain activity preceding a 2D manual catching task.

We investigated the event-related desynchronization (ERD) and synchronization (ERS) properties of cortical EEG rhythms in regions of interest (ROI) during the preparation of a 2D task for manual catching of a moving object. EEG signals were recorded through a 32-channel system in eleven healthy subjects during the interception task consisting of 2D catching with the right hand of a handle moving at constant velocity (1.5 m/s) on a predefined straight trajectory. The first session of catching movements (CATCHING_PRE) was compared with a second session after 1 h with identical characteristics (CATCHING_POST) and with other two conditions, where the subjects had to reach and grasp the handle fixed in the medium of platform (REACHING) and they looked at the object moving without catching it (GAZE TRACKING). Changes of cortical rhythms were correlated with dynamic and kinematic indexes of motor performance in both catching sessions. Movements requiring different strategies (predictive versus prospective) are supported by specific changes of cortical EEG rhythms: in the CATCHING condition a more evident power decrease (ERD) in alpha 2 and beta band in the sensorimotor region contralateral to the catching hand was observed, while in the REACHING one a bilateral ERD in beta band was found. Motor learning and movement automatization were characterized by a significant reduction of theta ERS in the anterior cingulate cortex (ACC), a ROI linked to focused attention, and with a shift of neuronal activation in alpha 2 band from the bilateral superior parietal areas to the homologous area of the left hemisphere. Finally, our EEG findings are consistent with the role of supplementary motor (SMA), premotor and prefrontal areas in motor planning and preparation. In particular, theta ERS in left SMA significantly correlated with an improvement of motor performance, as evidenced by its correlation with the training-related reduction of interception time (IT).

Inter-hemispheric coupling changes associate with motor improvements after robotic stroke rehabilitation

PURPOSEnIn the chronic phase of stroke brain plasticity plays a crucial role for further motor control improvements. This study aims to assess the brain plastic reorganizations and their association with clinical progresses induced by a robot-aided rehabilitation program in chronic stroke patients.nnnMETHODSn7 stroke patients with an upper limb motor impairment in chronic phase underwent a multi-modal evaluation before starting and at the end of a 12-week upper-limb neurorehabilitation program. Fugl-Meyer Assessment (FMA) Scale scores and performance indices of hand movement performance (isometric pinch monitored through a visual feedback) were collected. Cerebral reorganizations were characterized by 32-channel electroencephalography (EEG) focusing on ipsilesional and contralesional resting state properties investigating both bipolar derivations overlying the middle cerebral artery territory and the primary somatosensory sources (S1) obtained through the Functional Source Separation (FSS) method. Power Spectral Density (PSD) and interhemispheric coherence (IHCoh) at rest were measured and correlated with clinical and hand control robot-induced improvements.nnnRESULTSnAfter the robotic rehabilitation we found an improvement of FMAS scores and hand motor control performance and changes of brain connectivity in high frequency rhythms (24-90 Hz). In particular, the improvement of motor performance correlated with the modulation of the interhemispheric S1 coherence in the high beta band (24-33 Hz).nnnCONCLUSIONSnRecently it has been shown that an upper limb robot-based rehabilitation improves motor performance in stroke patients. We confirm this potential and demonstrate that a robot-aided rehabilitation program induces brain reorganizations. Specifically, interhemispheric connectivity between primary somatosensory areas got closer to a physiological level in parallel with the acquisition of more accurate hand control.

Immediate and Late Modulation of Interhemipheric Imbalance With Bilateral Transcranial Direct Current Stimulation in Acute Stroke

BACKGROUNDnSignificant changes in neurophysiological and clinical outcomes in chronic stroke had been reported after tDCS; but there is a paucity of data in acute stroke.nnnOBJECTIVEnWe aimed to evaluate whether a tDCS-induced modulation of primary motor cortex excitability in patients with acute stroke enhances motor recovery associated with rehabilitation and induces differential neuroplasticity.nnnMETHODSnWe conducted two experiments in acute stroke patients. In experiment 1 (14 patients), we tested the immediate effects of bilateral tDCS alone as compared to sham tDCS on recovery. Experiment 2 (20 patients) was designed to assess effects of bilateral tDCS delivered together with constraint-induced movement therapy (CIMT). In this experiment, we included a longer follow-up (3 months) and measured, in addition to the same clinical outcomes of experiment 1, changes of motor cortex excitability and the amount of promoted LTP-like activity.nnnRESULTSnDespite the expected improvement at 1 week, none of the clinical measures showed any different modulation in dependence of CIMT and tDCS. On the neurophysiological assessments, on the other hand, the Real_tDCS group, compared to Sham_tDCS group, showed a reduction of inter-hemispheric imbalance when considering the differences of motor evoked potential between both 3-month and 1 week follow up (P = 0.007) and three month and baseline (P = 0.015).nnnCONCLUSIONSnDespite the lack of additional clinical changes, real bilateral tDCS, together with CIMT, significantly reduces inter-hemispheric imbalance between affected and unaffected hemispheres. These findings may shed light on plasticity changes in acute stroke and its potential impact in chronic phases.

Bringing transcranial mapping into shape: Sulcus-aligned mapping captures motor somatotopy in human primary motor hand area

Motor representations express some degree of somatotopy in human primary motor hand area (M1HAND), but within-M1HAND corticomotor somatotopy has been difficult to study with transcranial magnetic stimulation (TMS). Here we introduce a linear TMS mapping approach based on the individual shape of the central sulcus to obtain mediolateral corticomotor excitability profiles of the abductor digiti minimi (ADM) and first dorsal interosseus (FDI) muscles. In thirteen young volunteers, we used stereotactic neuronavigation to stimulate the right M1HAND with a small eight-shaped coil at 120% of FDI resting motor threshold. We pseudorandomly stimulated six targets located on a straight mediolateral line corresponding to the overall orientation of the central sulcus with a fixed coil orientation of 45° to the mid-sagittal line (STRAIGHT-450FIX) or seven targets in the posterior part of the crown of the central sulcus following the bending of the central sulcus (CURVED). CURVED mapping employed a fixed (CURVED-450FIX) or flexible coil orientation producing always a current perpendicular to the sulcal wall (CURVED-900FLEX). During relaxation, CURVED but not STRAIGHT mapping revealed distinct corticomotor excitability peaks in M1HAND with the excitability maximum of ADM located medially to the FDI maximum. This mediolateral somatotopy was still present during tonic contraction of the ADM or FDI. During ADM contraction, cross-correlation between the spatial excitability profiles of ADM and FDI was lowest for CURVED-900FLEX. Together, the results show that within-M1HAND somatotopy can be readily probed with linear TMS mapping aligned to the sulcal shape. Sulcus-aligned linear mapping will benefit non-invasive studies of representational plasticity in human M1HAND.

Val66Met BDNF gene polymorphism influences human motor cortex plasticity in acute stroke.

BACKGROUNDnBDNF gene polymorphism impacts human motor cortex function and plasticity.nnnOBJECTIVE/HYPOTHESISnUsing transcranial magnetic stimulation (TMS), we investigated whether BDNF polymorphism influences cortical plastic changes in acute stroke.nnnMETHODSnTwenty patients were recruited within 10 days of their first-ever ischemic stroke and genotyped for BDNF polymorphism. Blinded to the latter, we evaluated the excitability of the affected and unaffected hemisphere by measuring resting and active motor threshold and motor-evoked potential amplitude under baseline conditions and after intermittent theta burst stimulation, a protocol of repetitive TMS inducing LTP-like activity. We also computed laterality indexes to assess inter-hemispheric excitability imbalance.nnnRESULTSnDemographics, threshold and amplitude of motor-evoked potentials did not differ between those with (8 patients) and without polymorphism. Excitability of the unaffected hemisphere was significantly higher than the excitability of the affected hemisphere as probed by each measure. This imbalance was exaggerated in those without polymorphism; laterality indexes of rest motor thresholds were 0.016xa0±xa00.050 and 0.139xa0±xa00.028 for patients with and without polymorphism [txa0=xa02.270, Pxa0=xa00.036]. Exaggerated hemispheric imbalance also persisted after intermittent theta burst stimulation, which failed to induce any difference between groups.nnnCONCLUSIONSnOur results suggest that inter-hemispheric imbalance with greater excitability over unaffected hemisphere, is several times stronger in stroke patients without, as opposed to with, polymorphism.

Wakefulness delta waves increase after cortical plasticity induction

OBJECTIVEnDelta waves (DW) are present both during sleep and in wakefulness. In the first case, DW are considered effectors of synaptic plasticity, while in wakefulness, when they appear in the case of brain lesions, their functional meaning is not unanimously recognized. To throw light on the latter, we aimed to investigate the impact on DW exerted by the cortical plasticity-inducing protocol of intermittent theta burst stimulation (iTBS).nnnMETHODSnTwenty healthy subjects underwent iTBS (11 real iTBS and nine sham iTBS) on the left primary motor cortex with the aim of inducing long-term potentiation (LTP)-like phenomena. Five-minute resting open-eye 32-channel EEG, right opponens pollicis motor-evoked potentials (MEPs), and alertness behavioral scales were collected before and up to 30 min after the iTBS. Power spectral density (PSD), interhemispheric coherence between homologous sensorimotor regions, and intrahemispheric coherence were calculated for the frequency bands ranging from delta to beta.nnnRESULTSnReal iTBS induced a significant increase of both MEP amplitude and DW PSD lasting up to 30 min after stimulation, while sham iTBS did not. The DW increase was evident over frontal areas ipsilateral and close to the stimulated cortex (electrode F3). Neither real nor sham iTBS induced significant modifications in the PSD of theta, alpha, and beta bands and in the interhemispheric coherence. Behavioral visuo-analogic scales score did not demonstrate changes in alertness after stimulations. No correlations were found between MEP amplitude and PSD changes in the delta band.nnnCONCLUSIONSnOur data showed that LTP induction in the motor cortex during wakefulness, by means of iTBS, is accompanied by a large and enduring increase of DW over the ipsilateral frontal cortex.nnnSIGNIFICANCEnThe present results are strongly in favor of a prominent role of DW in the neural plasticity processes taking place during the awake state.

Oral fingolimod reduces glutamate-mediated intracortical excitability in relapsing-remitting multiple sclerosis

OBJECTIVEnFingolimod is an effective disease modifying therapy for multiple sclerosis (MS). Beyond its main action on peripheral lymphocytes, several noteworthy side effects have been demonstrated in vitro, among which modulation of neural excitability. Our aim was to explore cortical excitability in vivo in patients treated with fingolimod 0.5mg/day.nnnMETHODSnPaired-pulse TMS was applied on the left primary motor cortex in 13 patients affected by relapsing-remitting MS, the day before the first dose of fingolimod (T0) and 60days later (T1). Resting motor threshold, baseline motor evoked potentials, short interval intracortical inhibition (at 1, 3, 5ms) and intracortical facilitation (at 7, 9, 11 and 13ms) were estimated at T0 and T1.nnnRESULTSnIntracortical facilitation was reduced at T1, without any changes in short interval intracortical inhibition.nnnCONCLUSIONSnFingolimod selectively reduced intracortical facilitation, which is mainly mediated by glutamate.nnnSIGNIFICANCEnThis is the first in vivo confirmation of the effects of fingolimod on glutamatergic drive in treated humans. Our results suggest a novel neuromodulatory activity of fingolimod with potential effect on glutamate-mediated excitotoxicity in vivo, as already seen in animal models.

The Effect of Cerebellar Degeneration on Human Sensori-motor Plasticity

BACKGROUNDnPlasticity of the primary motor cortex (M1) has a critical role in motor control and learning. The cerebellum facilitates these functions using sensory feedback.nnnOBJECTIVEnWe investigated how cerebellar degeneration influences the plasticity of the M1 by using PAS (paired associative stimulation) technique. PAS involves repeated pairs of electrical stimuli to the median nerve and transcranial magnetic stimulation (TMS) of the motor cortex. If the interval between peripheral and TMS stimulation is around 21-25xa0ms, corticospinal excitability is increased via a long term potentiation (LTP)-like effect within M1. Our aims were: (i) to explore the presence of a time-specific influence of cerebellar degeneration on human associative plasticity; (ii) to evaluate the role played by somatosensory pathway on cerebellar modulation of sensory-motor plasticity.nnnMETHODSnWe studied 10 patients with pure cerebellar atrophy and 10 age-matched healthy subjects. Motor-evoked-potentials amplitudes, short-afferent inhibition (SAI), motor thresholds, I/O curves, somatosensory-evoked-potential (SEP) were measured before, just after and 30xa0min after PAS at ISIs (interstimulus intervals) of 21.5 and 25xa0ms.nnnRESULTSnCerebellar patients show a selective lack of LTP-like effect induced by PAS25xa0ms, but not at 21.5xa0ms. SAI was overall not truly modulated by PAS but clearly differed between cerebellar patients and healthy subjects for ISIs around 25xa0ms (+6xa0ms andxa0+8xa0ms) (Pxa0<xa00.01). SEPs showed the amplitude of P25 wave was markedly reduced in patients with a more severe clinical and radiological impairment of cerebellum.nnnCONCLUSIONSnCerebellar patients have an altered capability of cerebellar filtering or processing of time-specific incoming sensory volleys, influencing the plasticity of M1.

Detection and Magnetic Source Imaging of Fast Oscillations (40–160 Hz) Recorded with Magnetoencephalography in Focal Epilepsy Patients

AbstractWe present a framework to detect fast oscillations (FOs) in magnetoencephalography (MEG) and to perform magnetic source imaging (MSI) to determine the location and extent of their generators in the cortex. FOs can be of physiologic origin associated to sensory processing and memory consolidation. In epilepsy, FOs are of pathologic origin and biomarkers of the epileptogenic zone. Seventeen patients with focal epilepsy previously confirmed with identified FOs in scalp electroencephalography (EEG) were nevaluated. To handle data deriving from large number of sensors (275 axial gradiometers) we used an automatic detector with high sensitivity. False positives were discarded by two human experts. MSI of the FOs was performed with the wavelet based maximum entropy on the mean method. We found FOs in 11/17 patients, in only one patient the channel with highest FO rate was not concordant with the epileptogenic region and might correspond to physiologic oscillations. MEG FOs rates were very low: 0.02–4.55 per minute. Compared to scalp EEG, detection sensitivity was lower, but the specificity higher in MEG. MSI of FOs showed concordance or partial concordance with proven generators of seizures and epileptiform activity in 10/11 patients. We have validated the proposed framework for the non-invasive study of FOs with MEG. The excellent overall concordance with other clinical gold standard evaluation tools indicates that MEG FOs can provide relevant information to guide implantation for intracranial EEG pre-surgical evaluation and for surgical treatment, and demonstrates the important added value of choosing appropriate FOs detection and source localization methods.