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Interhemispheric Connectivity Characterizes Cortical Reorganization in Motor-Related Networks After Cerebellar Lesions

Authors:
  • INRIA & Institut du Cerveau et de la Moelle epiniere
  • Faculty of Medicine and Psychology, Sapienza University of Rome
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Abstract and Figures

Although cerebellar-cortical interactions have been studied extensively in animal models and humans using modern neuroimaging techniques, the effects of cerebellar stroke and focal lesions on cerebral cortical processing remain unknown. In the present study, we analyzed the large-scale functional connectivity at the cortical level by combining high-density electroencephalography (EEG) and source imaging techniques to evaluate and quantify the compensatory reorganization of brain networks after cerebellar damage. The experimental protocol comprised a repetitive finger extension task by 10 patients with unilateral focal cerebellar lesions and 10 matched healthy controls. A graph theoretical approach was used to investigate the functional reorganization of cortical networks. Our patients, compared with controls, exhibited significant differences at global and local topological level of their brain networks. An abnormal rise in small-world network efficiency was observed in the gamma band (30–40 Hz) during execution of the task, paralleled by increased long-range connectivity between cortical hemispheres. Our findings show that a pervasive reorganization of the brain network is associated with cerebellar focal damage and support the idea that the cerebellum boosts or refines cortical functions. Clinically, these results suggest that cortical changes after cerebellar damage are achieved through an increase in the interactions between remote cortical areas and that rehabilitation should aim to reshape functional activation patterns. Future studies should determine whether these hypotheses are limited to motor tasks or if they also apply to cerebro-cerebellar dysfunction in general.
Patient characteristics and experimental protocol. a Each individual lesion is presented overlaid on coronal T1-weighted template from Schmahmann et al. [132]. Case codes as in Table 1. Cerebellar lesions were first drawn on every patient’s 3D MPRAGE in native space using MRIcro (http://www.sph.sc.edu/comd/rorden/mricro.html), thus creating a lesion mask. The 3D T1-mprage images were processed by using SPM2 (Wellcome Dept. Cogn. Neurol., London; http://www.fil.ion.ucl.ac.uk/spm). For each subject, images were manually reoriented according to the default template in SPM2 and then normalized into the standard proportional stereotaxic space [Montreal Neurological Institute (MNI)]. b Two conditions were considered: affected hand condition and unaffected hand. In case of subjects with right cerebellar lesion (n = 7 representative subject CB4 is depicted at the bottom), the left cortical hemisphere (colored in red) would be deprived from the cerebellar input and thus movement of contralateral right hand would represent the affected hand condition. Conversely, left hand movement would correspond to the unaffected hand condition. For subjects with left cerebellar lesion (n = 3), left hand movement would represent the affected hand condition and right hand movement would represent the unaffected hand condition. c Two periods of interest were considered in the study corresponding to the preparation (PRE) and execution (EXE) phase of the hand motor task. These periods were segmented from the EMG onset and their duration was fixed to 500 ms
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ORIGINAL PAPER
Interhemispheric Connectivity Characterizes Cortical
Reorganization in Motor-Related Networks
After Cerebellar Lesions
Fabrizio De Vico Fallani
1,2
&Silvia Clausi
3,4
&Maria Leggio
3,4
&Mario Chavez
2
&
Miguel Valencia
5,6
&Anton Giulio Maglione
3
&Fabio Babiloni
7,3
&Febo Cincotti
8,3
&
Donatella Mattia
3
&Marco Molinari
3
Published online: 2 July 2016
#Springer Science+Business Media New York 2016
Abstract Although cerebellar-cortical interactions have been
studied extensively in animal models and humans using mod-
ern neuroimaging techniques, the effects of cerebellar stroke
and focal lesions on cerebral cortical processing remain un-
known. In the present study, we analyzed the large-scale func-
tional connectivity at the cortical level by combining high-
density electroencephalography (EEG) and source imaging
techniques to evaluate and quantify the compensatory reorga-
nization of brain networks after cerebellar damage. The exper-
imental protocol comprised a repetitive finger extension task
by 10 patients with unilateral focal cerebellar lesions and 10
matched healthy controls. A graph theoretical approach was
used to investigate the functional reorganization of cortical
networks. Our patients, compared with controls, exhibited
significant differences at global and local topological level
of their brain networks. An abnormal rise in small-world net-
work efficiency was observed in the gamma band (3040 Hz)
during execution of the task, paralleled by increased long-
range connectivity between cortical hemispheres. Our find-
ings show that a pervasive reorganization of the brain network
is associated with cerebellar focal damage and support the idea
that the cerebellum boosts or refines cortical functions.
Clinically, these results suggest that cortical changes after cer-
ebellar damage are achieved through an increase in the inter-
actions between remote cortical areas and that rehabilitation
should aim to reshape functional activation patterns. Future
studies should determine whether these hypotheses are limited
to motor tasks or if they also apply to cerebro-cerebellar dys-
function in general.
Keywords Graph theory .Cerebellum .EEG .Functional
connectivity .Brain plasticity
Introduction
Functional recovery after stroke is associated with anatomic
and functional changes in the brain [13]. Commonly, brain-
healing mechanisms occur spontaneously after stroke and can
lead to some initial functional recovery of injured brain areas.
Then, functional changes in non-injured regions can intervene
in supporting compensatory mechanisms. In the last years,
advances in computational neuroscience and brain imaging
techniques have served to supervise in vivo some of these
organizational, system-level, processes by means of graph
theoretic approaches [4,5] fMRI, magnetoencephalography
(MEG), and electroencephalography (EEG) studies have
Electronic supplementary material The online version of this article
(doi:10.1007/s12311-016-0811-z) contains supplementary material,
which is available to authorized users.
*Marco Molinari
m.molinari@hsantalucia.it
1
Inria Paris, ARAMIS project-team, Paris, France
2
ICM, CNRS UMR 7225, Inserm U1127, Sorbonne Universités
UPMC S1127, Paris, France
3
IRCCS BFondazione Santa Lucia^, Via Ardeatina, 309,
00179 Rome, Italy
4
Department of Psychology, Sapienza University of Rome,
Rome, Italy
5
Neurosciences Area, CIMA, Universidad de Navarra,
31008 Pamplona, Spain
6
IdiSNA, Navarra Institute for Health Research,
31008 Pamplona, Spain
7
Departement of Molecular Medicine, Sapienza University of Rome,
Rome, Italy
8
DIAG, Sapienza University of Rome, Rome, Italy
Cerebellum (2017) 16:358375
DOI 10.1007/s12311-016-0811-z
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... In this regard, it has been demonstrated via EEG graph analysis that an ischemic stroke is responsible for a bi-hemispheric brain network rearrangement showing a frequency-dependent modality (Caliandro et al., 2017). While the plasticity alterations induced by hemispheric strokes have already been described in terms of anatomical, functional and effective connectivity changes, the brain modifications due to an acute ischemic cerebellar lesion received less attention (De Vico et al., 2017), although the cerebellum is known to be involved in motor control processes and coordination (Kornhuber, 1978;Ramnani et al., 2001), cognitive functions (Kim et al., 1994), learning and relearning mechanisms (Ivry and Baldo, 1992;Allen et al., 1997), all of them playing a pivotal role in the recovery after stroke. It is noteworthy that the cerebellum and cortical areas are widely anatomically interconnected: as for the anatomical routes, cortico-ponto-cerebellar projections form part of a closed loop system with the cerebral cortex, in which the cerebellum returns projections mainly to the contralateral cerebral cortex -namely the motor one-via the thalamus (Asanuma et al., 1983;Schmahmann and Pandya, 1997;Middleton and Strick, 1997;Ramnani, 2006). ...
... It is reasonable to hypothesize that the right beta 2 Sw modulation could be somehow linked to the composition of our sample, where there is a prevalence of patients with left cerebellar lesion. It is interesting to underline that our findings on increased beta 2 and gamma Sw in resting-state condition is similar to those observed in patients with different focal cerebellar lesions during the performance of a finger task (De Vico et al., 2017). De Vico and colleagues found an increased Sw in beta 2 and gamma bands during the execution of the task either with the affected or with the unaffected hand and found no correlation between the graph indexes and the clinical picture, specifically the motor performance (ICARS), general intelligence (IQWAIS-R), and Z-cognitive scores. ...
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Objective: We tested whether acute cerebellar stroke may determine changes in brain network architecture as defined by cortical sources of EEG rhythms. Methods: Graph parameters of 41 consecutive stroke patients (<5 days from the event) were studied using eLORETA EEG sources. Network rearrangements of stroke patients were investigated in delta, alpha 2, beta 2 and gamma bands in comparison with healthy subjects. Results: The delta network remodeling was similar in cerebellar and middle cerebral artery strokes, with a reduction of small-worldness. Beta 2 and gamma small-worldness, in the right hemisphere of patients with cerebellar stroke, increase respect to healthy subjects, while alpha 2 small-worldness increases only among patients with a middle cerebral artery stroke. Conclusions: The network remodeling characteristics are independent on the size of the ischemic lesion. In the early post-acute stages cerebellar stroke differs from the middle cerebral artery one because it does not cause alpha 2 network remodeling while it determines a high frequency network reorganization in beta 2 and gamma bands with an increase of small-worldness characteristics. Significance: These findings demonstrate changes in the balance of local segregation and global integration induced by cerebellar acute stroke in high EEG frequency bands. They need to be integrated with appropriate follow-up to explore whether further network changes are attained during post-stroke outcome stabilization.
... On the one hand, a typical finding in stroke connectivity studies is decreased functional connectivity (FC) in the perilesional area, which is observed shortly after the insult and slowly resolves with time; a process predicting recovery (Westlake et al., 2012). On the other hand, increased FC has been observed after stroke expressed as an increase in small-world network efficiency in the gamma frequency band and an increase in the interhemispheric connectivity in stroke patients during a simple finger extension task (De Vico Fallani et al., 2016). There may be complex relationships between structural connectivity and FC following a stroke, including reduced M1 fractional anisotropy (structural connectivity) in the anatomical connection between M1 of both hemispheres, which is accompanied by increased resting state FC between the same two structures, thereby suggesting that the activity is somewhat compensatory to structural damage . ...
... An additional inhibitory pathway leading from the contralesional to the ipsilesional M1 has also been found in another study in stroke patients, and was correlated with worse motor function (Grefkes et al., 2008). Connectivity increases between the ipsilesional M1 and contralesional M1 were noted in many studies De Vico Fallani et al., 2016;Liu et al., 2016;Zhang et al., 2016) and were interpreted as a proof for the contralateral disinhibition theory (von Carlowitz-Ghori et al., 2014;Volz et al., 2015). Analysing the connectivity in different time points may suggest that the imbalance of inhibition is a dynamic restorative mechanism, which may play an adaptive role at a specific moment during recovery. ...
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Recovery from a stroke is a dynamic time-dependent process, in which the central nervous system reorganises to accommodate for the impact of the injury. The purpose of this paper is to review recent longitudinal studies of changes in brain connectivity after stroke. A systematic review of research papers reporting functional or effective connectivity at two or more time points in stroke patients was conducted. Stroke leads to an early reduction of connectivity in the motor network. With recovery time, the connectivity increases and can reach the same levels as in healthy participants. The increase in connectivity is correlated with functional motor gains. A new, more randomised pattern of connectivity may then emerge in the longer term. In some instances, a pattern of increased connectivity even higher than in healthy controls can be observed, and is related either to a specific time point or to a specific neural structure. Rehabilitation interventions can help improve connectivity between specific regions. Moreover, motor network connectivity undergoes reorganisation during recovery from a stroke and can be related to behavioural recovery. A detailed analysis of changes in connectivity pattern may enable a better understanding of adaptation to a stroke and how compensatory mechanisms in the brain may be supported by rehabilitation.
... Only Zeng et al. [14] and Caliandro et al. [15] compared the features of the EEGs collected at the impaired zones with the those recorded at the healthy zones: Caliandro et al. [15] observed no difference between the two hemispheres of the same subject, whereas Zeng et al. [14] claimed that the method they proposed needed to be further validated on EEG time series. As regards high-density EEG studies, De Vico Fallani et al. [18] applied source imaging to HD-EEG to evaluate the compensatory reorganization of brain networks after cerebellar damage during a finger extension task. Sixty-four-channel EEGs were acquired during alternating movement tasks. ...
... The subjects kept their eyes closed but remained awake (eye-closed resting state) during EEG acquisition. EEG signals were bandpass-filtered between 1 and 40 Hz by the Net Station EEG software, which comes with the Electrical Geodesics EEG system, to include the major EEG waves: delta (1-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), beta (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and gamma (>30 Hz). Once filtered, the recordings were manually reviewed by the EEG experts to mark and discard the artifactual segments. ...
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Stroke is a critical event that causes the disruption of neural connections. There is increasing evidence that the brain tries to reorganize itself and to replace the damaged circuits, by establishing compensatory pathways. Intra- and extra-cellular currents are involved in the communication between neurons and the macroscopic effects of such currents can be detected at the scalp through electroencephalographic (EEG) sensors. EEG can be used to study the lesions in the brain indirectly, by studying their effects on the brain electrical activity. The primary goal of the present work was to investigate possible asymmetries in the activity of the two hemispheres, in the case one of them is affected by a lesion due to stroke. In particular, the compressibility of High-Density-EEG (HD-EEG) recorded at the two hemispheres was investigated since the presence of the lesion is expected to impact on the regularity of EEG signals. The secondary objective was to evaluate if standard low density EEG is able to provide such information. Eighteen patients with unilateral stroke were recruited and underwent HD-EEG recording. Each EEG signal was compressively sensed, using Block Sparse Bayesian Learning, at increasing compression rate. The two hemispheres showed significant differences in the compressibility of EEG. Signals acquired at the electrode locations of the affected hemisphere showed a better reconstruction quality, quantified by the Structural SIMilarity index (SSIM), than the EEG signals recorded at the healthy hemisphere (p < 0.05), for each compression rate value. The presence of the lesion seems to induce an increased regularity in the electrical activity of the brain, thus an increased compressibility.
... Then, the connectivity progressively increases during the subacute and chronic phases towards pre-stroke coupling levels, documenting a reorganization of resting-state networks (Thiel and Vahdat, 2015). These observations were found using both undirected and directed functional connectivity, exploiting both fMRI (Carter et al., 2009;Van Meer et al., 2010;Wang et al., 2010;Siegel et al., 2016Siegel et al., , 2018Caliandro et al., 2017;Adhikari et al., 2021) and EEG signals (Pichiorri et al., 2015(Pichiorri et al., , 2018De Vico Fallani et al., 2017). ...
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... Furthermore, blocking BDNF via gene mutations or neutralization of antibodies can notably reduce the expression of cyclic adenosine monophosphate response-element-binding protein, and then eliminate exercise-induced recovery of motor learning memory (Ploughman et al., 2009). Exercise training has been found to promote plastic changes in the damaged motor network, specifically in M1, the premotor cortex, and the posterior parietal cortex (Youssofzadeh et al., 2016;De Vico Fallani et al., 2017). Physical exercise, particularly in paretic limbs, could reduce activity in the contralesional M1 and alter the activity of related brain regions (Barbay et al., 2013). ...
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Physical exercise can minimize dysfunction and optimize functional motor recovery after stroke by modulating cortical plasticity. However, the limitation of physical exercise is that large amounts of time and effort are necessary to significantly improve motor function, and even then, substantial exercise may not be sufficient to normalize the observed improvements. Thus, interventions that could be used to strengthen physical exercise-induced neuroplasticity may be valuable in treating hemiplegia after stroke. Repetitive transcranial magnetic stimulation seems to be a viable strategy for enhancing such plasticity. As a non-invasive cortical stimulation technique, repetitive transcranial magnetic stimulation is able to induce long-term plastic changes in the motor system. Recently, repetitive transcranial magnetic stimulation was found to optimize the plastic changes caused by motor training, thereby enhancing the long-term effects of physical exercise in stroke patients. Therefore, it is believed that the combination of repetitive transcranial magnetic stimulation and physical exercise may represent a superior method for restoring motor function after stroke.
... This s-MMN paradigm was studied in subjects with unilateral cerebellar lesions to exploit the possibility of testing cortical responses with and without cerebellar processing in the same subject. Because of the well-known crossed organization of cerebro-cerebellar circuits, unilateral cerebellar damage will affect only the cerebral cortex of the contralateral hemisphere (Di Lazzaro et al., 1994a,b, 1995De Vico Fallani et al., 2016). ...
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... Also more complex network effects are present. Recently, Fallani and colleagues could show, using high-density electroencephalography (EEG) and source imaging, that cerebellar lesions result in functional reorganization of cortical network properties [58]. ...
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The clinical benefits of targeting the ventral intermediate nucleus (VIM) for the treatment of tremors in essential tremor (ET) patients suggest that the VIM is a key hub in the network of tremor generation and propagation and that the VIM can be considered as a seed region to study the tremor network. However, little is known about the central tremor network in ET patients. Twenty-six ET patients and 26 matched healthy controls (HCs) were included in this study. After considering structural and head-motion factors and establishing the accuracy of our seed region, a VIM seed-based functional connectivity (FC) analysis of resting-state functional magnetic resonance imaging (RS-fMRI) data was performed to characterize the VIM FC network in ET patients. We found that ET patients and HCs shared a similar VIM FC network that was generally consistent with the VIM anatomical connectivity network inferred from normal nonhuman primates and healthy humans. Compared with HCs, ET patients displayed VIM-related FC changes, primarily within the VIM-motor cortex (MC)-cerebellum (CBLM) circuit, which included decreased FC in the CBLM and increased FC in the MC. Importantly, tremor severity correlated with these FC changes. These findings provide the first evidence that the pathological tremors observed in ET patients might be based on a physiologically pre-existing VIM - MC - CBLM network and that disruption of FC in this physiological network is associated with ET. Further, these findings demonstrate a potential approach for elucidating the neural network mechanisms underlying this disease. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc.
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Valid biomarkers of motor system function after stroke could improve clinical decision-making. Electroencephalography-based measures are safe, inexpensive, and accessible in complex medical settings and so are attractive candidates. This study examined specific electroencephalography cortical connectivity measures as biomarkers by assessing their relationship with motor deficits across 28 days of intensive therapy. Resting-state connectivity measures were acquired four times using dense array (256 leads) electroencephalography in 12 hemiparetic patients (7.3 ± 4.0 months post-stroke, age 26-75 years, six male/six female) across 28 days of intensive therapy targeting arm motor deficits. Structural magnetic resonance imaging measured corticospinal tract injury and infarct volume. At baseline, connectivity with leads overlying ipsilesional primary motor cortex (M1) was a robust and specific marker of motor status, accounting for 78% of variance in impairment; ipsilesional M1 connectivity with leads overlying ipsilesional frontal-premotor (PM) regions accounted for most of this (R(2) = 0.51) and remained significant after controlling for injury. Baseline impairment also correlated with corticospinal tract injury (R(2) = 0.52), though not infarct volume. A model that combined a functional measure of connectivity with a structural measure of injury (corticospinal tract injury) performed better than either measure alone (R(2) = 0.93). Across the 28 days of therapy, change in connectivity with ipsilesional M1 was a good biomarker of motor gains (R(2) = 0.61). Ipsilesional M1-PM connectivity increased in parallel with motor gains, with greater gains associated with larger increases in ipsilesional M1-PM connectivity (R(2) = 0.34); greater gains were also associated with larger decreases in M1-parietal connectivity (R(2) = 0.36). In sum, electroencephalography measures of motor cortical connectivity-particularly between ipsilesional M1 and ipsilesional premotor-are strongly related to motor deficits and their improvement with therapy after stroke and so may be useful biomarkers of cortical function and plasticity. Such measures might provide a biological approach to distinguishing patient subgroups after stroke. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Article
Although cerebellar lesions do not cause evident sensory deficits, it has been suggested recently that the cerebellum might play a role in sensory acquisition and discrimination. To determine whether the cerebellum influences the early phases of cortical somatosensory processing, we recorded cortical somatosensory evoked potentials after median nerve stimulation in five patients with unilateral cerebellar damage. We also performed a dipolar source analysis of traces by means of brain electrical source analysis. In all patients, the amplitude of the frontal N24 and parietal P24 components, as well as the strength of the corresponding dipolar sources, were significantly smaller after stimulation of the symptomatic side. These neurophysiological findings indicate that the primary somatosensory cortical processing is altered after contralateral cerebellar damage. They represent the first indication of a possible substrate for the reduction in cerebral blood flow observed in the parietal cortex after cerebellar lesion. Furthermore, the present data allow characterization of the functional influence of the cerebellar input to the primary somatosensory cortex as specifically acting over the inhibitory components of somatosensory processing.