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

  • 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 (, thus creating a lesion mask. The 3D T1-mprage images were processed by using SPM2 (Wellcome Dept. Cogn. Neurol., London; 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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Interhemispheric Connectivity Characterizes Cortical
Reorganization in Motor-Related Networks
After Cerebellar Lesions
Fabrizio De Vico Fallani
&Silvia Clausi
&Maria Leggio
&Mario Chavez
Miguel Valencia
&Anton Giulio Maglione
&Fabio Babiloni
&Febo Cincotti
Donatella Mattia
&Marco Molinari
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
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
Inria Paris, ARAMIS project-team, Paris, France
ICM, CNRS UMR 7225, Inserm U1127, Sorbonne Universités
UPMC S1127, Paris, France
IRCCS BFondazione Santa Lucia^, Via Ardeatina, 309,
00179 Rome, Italy
Department of Psychology, Sapienza University of Rome,
Rome, Italy
Neurosciences Area, CIMA, Universidad de Navarra,
31008 Pamplona, Spain
IdiSNA, Navarra Institute for Health Research,
31008 Pamplona, Spain
Departement of Molecular Medicine, Sapienza University of Rome,
Rome, Italy
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. ...
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. ...
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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Brain plasticity and functional reorganization are mechanisms behind functional motor recovery of patients after an ischemic stroke. The study of resting-state motor network functional connectivity by means of EEG proved to be useful in investigating changes occurring in the information flow and find correlation with motor function recovery. In the literature, most studies applying EEG to post-stroke patients investigated the undirected functional connectivity of interacting brain regions. Quite recently, works started to investigate the directionality of the connections and many approaches or features have been proposed, each of them being more suitable to describe different aspects, e.g., direct or indirect information flow between network nodes, the coupling strength or its characteristic oscillation frequency. Each work chose one specific measure, despite in literature there is not an agreed consensus, and the selection of the most appropriate measure is still an open issue. In an attempt to shed light on this methodological aspect, we propose here to combine the information of direct and indirect coupling provided by two frequency-domain measures based on Granger’s causality, i.e., the directed coherence (DC) and the generalized partial directed coherence (gPDC), to investigate the longitudinal changes of resting-state directed connectivity associated with sensorimotor rhythms α and β, occurring in 18 sub-acute ischemic stroke patients who followed a rehabilitation treatment. Our results showed a relevant role of the information flow through the pre-motor regions in the reorganization of the motor network after the rehabilitation in the sub-acute stage. In particular, DC highlighted an increase in intra-hemispheric coupling strength between pre-motor and primary motor areas, especially in ipsi-lesional hemisphere in both α and β frequency bands, whereas gPDC was more sensitive in the detection of those connection whose variation was mostly represented within the population. A decreased causal flow from contra-lesional premotor cortex towards supplementary motor area was detected in both α and β frequency bands and a significant reinforced inter-hemispheric connection from ipsi to contra-lesional pre-motor cortex was observed in β frequency. Interestingly, the connection from contra towards ipsilesional pre-motor area correlated with upper limb motor recovery in α band. The usage of two different measures of directed connectivity allowed a better comprehension of those coupling changes between brain motor regions, either direct or mediated, which mostly were influenced by the rehabilitation, revealing a particular involvement of the pre-motor areas in the cerebral functional reorganization.
... 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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Optimal control mechanisms require prediction capabilities. If one cannot predict the consequences of a motor act or behavior, one will continually collide with walls or become a social pariah. “Looking into the future” is thus one of the most important prerequisites for smooth movements and social interactions. To achieve this goal, the brain must constantly predict future events. This principle applies to all domains of information processing, including motor and cognitive control, as well as the development of decision-making skills, theory of mind, and virtually all cognitive processes. Sequencing is suggested to support the predictive capacity of the brain. To recognize that events are related, the brain must discover links among them in the spatiotemporal domain. To achieve this, the brain must often hold one event in working memory and compare it to a second one, and the characteristics of the two must be compared and correctly placed in space and time. Among the different brain structures involved in sequencing, the cerebellum has been proposed to have a central function. We have suggested that the operational mode of the cerebellum is based on “sequence detection” and that this process is crucial for prediction. Patterns of temporally or spatially structured events are conveyed to the cerebellum via the pontine nuclei and compared with actual ones conveyed through the climbing fibers olivary inputs. Through this interaction, data on previously encountered sequences can be obtained and used to generate internal models from which predictions can be made. This mechanism would allow the cerebellum not only to recognize sequences but also to detect sequence violations. Cerebellar pattern detection and prediction would thus be a means to allow feedforward control based on anticipation. We will argue that cerebellar sequencing allows implementation of prediction by setting the correct excitatory levels in defined brain areas to implement the adaptive response for a given pattern of stimuli that embeds sufficient information to be recognized as a previously encountered template. Here, we will discuss results from human and animal studies and correlate them with the present understanding of cerebellar function in cognition and behavior.
... 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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Non-invasive brain stimulation (NIBS) combined with behavioral training is a promising strategy to augment recovery after stroke. Current research efforts have been mainly focusing on primary motor cortex (M1) stimulation. However, the translation from proof-of-principle to clinical applications is not yet satisfactory. Possible reasons are the heterogeneous properties of stroke, generalization of the stimulation protocols, and hence the lack of patient stratification. One strategy to overcome these limitations could be the evaluation of alternative stimulation targets, like the cerebellum. In this regard, first studies provided evidence that non-invasive cerebellar stimulation can modulate cerebellar processing and linked behavior in healthy subjects. The cerebellum provides unique plasticity mechanisms and has vast connections to interact with neocortical areas. Moreover, the cerebellum could serve as a non-lesioned entry to the motor or cognitive system in supratentorial stroke. In the current article, we review mechanisms of plasticity in the cortico-cerebellar system after stroke, methods for non-invasive cerebellar stimulation, and possible target symptoms in stroke, like fine motor deficits, gait disturbance, or cognitive impairments, and discuss strategies for multi-focal stimulation.
... A number of studies have demonstrated that rTMS protocols could alter the activity and function of targeted brain region as well as its related remote regions (Jing and Takigawa, 2000;Plewnia et al., 2008;Grefkes et al., 2010). The activity of many cortices related to motor function, such as premotor, primary motor, and posterior parietal cortex can also be changed by MT (Youssofzadeh et al., 2016;De Vico Fallani et al., 2017). Instead of local regional activity, functional connectivity, which can be obtained through analysis of inter-regional coupling, reflects the functional interactions between the underlying brain regions (Ward and Cohen, 2004;Grefkes et al., 2010). ...
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It has recently been reported that repetitive transcranial magnetic stimulation combined with motor training (rTMS-MT) could improve motor function in post-stroke patients. However, the effects of rTMS-MT on cortical function using functional connectivity and graph theoretical analysis remain unclear. Ten healthy subjects were recruited to receive rTMS immediately before application of MT. Low frequency rTMS was delivered to the dominant hemisphere and non-dominant hand performed MT over 14 days. The reaction time of Nine-Hole Peg Test and electroencephalography (EEG) in resting condition with eyes closed were recorded before and after rTMS-MT. Functional connectivity was assessed by phase synchronization index (PSI), and subsequently thresholded to construct undirected graphs in alpha frequency band (8–13 Hz). We found a significant decrease in reaction time after rTMS-MT. The functional connectivity between the parietal and frontal cortex, and the graph theory statistics of node degree and efficiency in the parietal cortex increased. Besides the functional connectivity between premotor and frontal cortex, the degree and efficiency of premotor cortex showed opposite results. In addition, the number of connections significantly increased within inter-hemispheres and inter-regions. In conclusion, this study could be helpful in our understanding of how rTMS-MT modulates brain activity. The methods and results in this study could be taken as reference in future studies of the effects of rTMS-MT in stroke patients.
Importance: The cerebellum plays an important role in motor, cognitive, and affective functions owing to its dense interconnections with basal ganglia and cerebral cortex. This review aimed at summarizing the non-invasive cerebellar stimulation (NICS) approaches used to modulate cerebellar output and treat cerebellar dysfunction in the motor domain. Observation: The utility of NICS in the treatment of cerebellar and non-cerebellar neurological diseases (including Parkinson's disease, dementia, cerebellar ataxia, and stroke) is discussed. NICS induces meaningful clinical effects from repeated sessions alone in both cerebellar and non-cerebellar diseases. However, there are no conclusive data on this issue and several concerns need to be still addressed before NICS could be considered a valuable, standard therapeutic tool. Conclusions and relevance: Even though some challenges must be overcome to adopt NICS in a wider clinical setting, this tool might become a useful strategy to help patients with lesions in the cerebellum and cerebral areas that are connected with the cerebellum whether one could enhance cerebellar activity with the intention of facilitating the cerebellum and the entire, related network, rather than attempting to facilitate a partially damaged cortical region or inhibiting the homologs' contralateral area. The different outcome of each approach would depend on the residual functional reserve of the cerebellum, which is confirmed as a critical element to be probed preliminary in order to define the best patient-tailored NICS.
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Alzheimer’s disease causes alterations of the brain networks structure and function that can be modelized by a brain connectivity analyse.We proposed a multi-layer approach to analyse multi-frequency and multimodal brain networks built from magnetoencephalographic (MEG) recordings, functional (fMRI) or diffusion-weighted magnetic resonance imaging (DWI).Main results showed the existence of previously undefined type of hubs that are inter- frequency hubs; identified thanks to their multi-participation coefficient (MPC) computed from a brain connectivity network with a multi-frequency multiplex topology. These hubs are impacted by Alzheimer’s disease, which reduces their naturally high ability to integrate information propagating through different frequency bands.We also generalized the concept of core-periphery structure to multilayer networks to be able to apply it to a multimodal brain connectivity model that combines structural and functional networks in a single multiplex topology. Hence, we could identify, from a systemic point of view, the most important regions at the scale of the entire brain and study their alteration in patients with Alzheimer’s disease.Therefore, this thesis expose how multilayer networks applied to brain connectivity can help in understanding neurodegenerative diseases such as Alzheimer’s disease.
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OBJECT The dentatorubrothalamic tract (DRTT) is the major efferent cerebellar pathway arising from the dentate nucleus (DN) and decussating to the contralateral red nucleus (RN) and thalamus. Surprisingly, hemispheric cerebellar output influences bilateral limb movements. In animals, uncrossed projections from the DN to the ipsilateral RN and thalamus may explain this phenomenon. The aim of this study was to clarify the anatomy of the dentatorubrothalamic connections in humans. METHODS The authors applied advanced deterministic fiber tractography to a template of 488 subjects from the Human Connectome Project (Q1–Q3 release, WU-Minn HCP consortium) and validated the results with microsurgical dissection of cadaveric brains prepared according to Klingler’s method. RESULTS The authors identified the “classic” decussating DRTT and a corresponding nondecussating path (the nondecussating DRTT, nd-DRTT). Within each of these 2 tracts some fibers stop at the level of the RN, forming the dentatorubro tract and the nondecussating dentatorubro tract. The left nd-DRTT encompasses 21.7% of the tracts and 24.9% of the volume of the left superior cerebellar peduncle, and the right nd-DRTT encompasses 20.2% of the tracts and 28.4% of the volume of the right superior cerebellar peduncle. CONCLUSIONS The connections of the DN with the RN and thalamus are bilateral, not ipsilateral only. This affords a potential anatomical substrate for bilateral limb motor effects originating in a single cerebellar hemisphere under physiological conditions, and for bilateral limb motor impairment in hemispheric cerebellar lesions such as ischemic stroke and hemorrhage, and after resection of hemispheric tumors and arteriovenous malformations. Furthermore, when a lesion is located on the course of the dentatorubrothalamic system, a careful preoperative tractographic analysis of the relationship of the DRTT, nd-DRTT, and the lesion should be performed in order to tailor the surgical approach properly and spare all bundles.
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Healthy aging (HA) is associated with certain declines in cognitive functions, even in individuals that are free of any process of degenerative illness. Functional magnetic resonance imaging (fMRI) has been widely used in order to link this age-related cognitive decline with patterns of altered brain function. A consistent finding in the fMRI literature is that healthy old adults present higher activity levels in some brain regions during the performance of cognitive tasks. This finding is usually interpreted as a compensatory mechanism. More recent approaches have focused on the study of functional connectivity, mainly derived from resting state fMRI, and have concluded that the higher levels of activity coexist with disrupted connectivity. In this review, we aim to provide a state-of-the-art description of the usefulness and the interpretations of functional brain connectivity in the context of HA. We first give a background that includes some basic aspects and methodological issues regarding functional connectivity. We summarize the main findings and the cognitive models that have been derived from task-activity studies, and we then review the findings provided by resting-state functional connectivity in HA. Finally, we suggest some future directions in this field of research. A common finding of the studies included is that older subjects present reduced functional connectivity compared to young adults. This reduced connectivity affects the main brain networks and explains age-related cognitive alterations. Remarkably, the default mode network appears as a highly compromised system in HA. Overall, the scenario given by both activity and connectivity studies also suggests that the trajectory of changes during task may differ from those observed during resting-state. We propose that the use of complex modeling approaches studying effective connectivity may help to understand context-dependent functional reorganizations in the aging process.
This chapter focuses on recent data on the laminar organization of intralaminar nuclei (IL)-cortical fibers and provides evidence of anatomical compartmentation within IL. The functional significance of the structural IL organization is discussed in relation to a hypothesis of IL relay activity. The IL presents a precise structural organization capable of highly specific integration of the different inputs. On physiological grounds, the main difference between IL and relay nuclei is their different roles in affecting cortical functions. IL is classically considered as the thalamic system capable of affecting cortical behavioral states while the relay nuclei are considered as the site for conveying specific information to the cortex. At least in terms of thalamocortical relationships, recent data are against the existence of the differences between IL and relay nuclei. Lesion and recording studies have shown that the rhythmic oscillatory activity during cortical synchronization is present throughout the thalamus under the conditional activity of the nucleus reticularis thalami. Although some recent evidence suggests possible differences among thalamic nuclei in affecting cortical synchronization, no indication exists supporting a functional segregation between IL and relay nuclei.
Neuronal activity in the gamma-band range was long considered a marker of object representation. However, scalp-recorded EEG activity in this range is contaminated by a miniature saccade-related muscle artifact. Independent component analysis (ICA) has been proposed as a method of removal of such artifacts. Alternatively, beamforming, a source analysis method in which potential sources of activity across the whole brain are scanned independently through the use of adaptive spatial filters, offers a promising method of accounting for the artifact without relying on its explicit removal. We present here the application of ICA-based correction to a previously published dataset. Then, using beamforming, we examine the effect of ICA correction on the scalp-recorded EEG signal and the extent to which genuine activity is recoverable before and after ICA correction. We find that beamforming attributes much of the scalp-recorded gamma-band signal before correction to deep frontal sources, likely the eye muscles, which generate the artifact related to each miniature saccade. Beamforming confirms that what is removed by ICA is predominantly this artifactual signal, and that what remains after correction plausibly originates in the visual cortex. Thus, beamforming allows researchers to confirm whether their removal procedures successfully removed the artifact. Our results demonstrate that ICA-based correction brings about general improvements in signal-to-noise ratio suggesting it should be used along with, rather than be replaced by, beamforming.
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.
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:
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.