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Intermittent Theta-Burst Stimulation of the Lateral Cerebellum Increases Functional Connectivity of the Default Network

Mark A. Halko, Faranak Farzan, Mark C. Eldaief, Jeremy D. Schmahmann, and Alvaro Pascual-Leone1 | The Journal of Neuroscience, 3 September 2014, 34(36): 12049-12056; doi: 10.1523/JNEUROSCI.1776-14.2014

Copyright © 2015 by the Society for Neuroscience. All rights reserved.

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Abstract and Introduction


Abstract

Cerebral cortical intrinsic connectivity networks share topographically arranged functional connectivity with the cerebellum. However, the contribution of cerebellar nodes to distributed network organization and function remains poorly understood. In humans, we applied theta-burst transcranial magnetic stimulation, guided by subject-specific connectivity, to regions of the cerebellum to evaluate the functional relevance of connections between cerebellar and cerebral cortical nodes in different networks. We demonstrate that changing activity in the human lateral cerebellar Crus I/II modulates the cerebral default mode network, whereas vermal lobule VII stimulation influences the cerebral dorsal attention system. These results provide novel insights into the distributed, but anatomically specific, modulatory impact of cerebellar effects on large-scale neural network function.

Introduction

The functions of the cerebellum were thought to be confined to motor control and thus that cerebellar lesions resulted exclusively in deficits of extremity coordination, balance, gait, clarity of speech, or eye movements. This view has been superseded by a more nuanced understanding of the role of the cerebellum in neurological and neuropsychiatric function. Patients with lesions of the cerebellar anterior lobe demonstrate findings of impaired movement control, whereas those with lesions confined to the cerebellar posterior lobe do not develop motor deficits but rather a constellation of problems in higher-order functions conceptualized as the cerebellar cognitive affective syndrome (Schmahmann and Sherman, 1998; Stoodley et al., 2010).

As in the cerebral hemispheres, the network nodes in the cerebellum are topographically arranged (Buckner et al., 2011). The default mode network was assigned multiple different locations in the cerebellum in early studies (Fox et al., 2005; Habas et al., 2009), but larger sample datasets have been able to define the cerebellar default network nodes more clearly within Crus I and Crus II of the cerebellar hemispheres (Krienen and Buckner, 2009; Buckner et al., 2011). The locations of the spontaneous activity correlations observed in the cerebellum and the cerebral cortex reflect known cerebro-cerebellar anatomical connections, such that, when lesions disrupt anatomical connectivity, functional connectivity is also lost (Lu et al., 2011). Thus, the cerebellar nodes of cortical networks are likely actively involved in network function.

We have shown previously that functional connectivity can be altered between the site of stimulation and other network nodes (Eldaief et al., 2011). This modulation was dependent on the frequency of stimulation, demonstrating a dose dependence of the effect. Transcranial magnetic stimulation (TMS) to a single region may not change connectivity between regions but rather only change the activity in a single location, which is reflected in the connectivity measurement between regions. Alternatively, TMS to a single region may alter functional connectivity within the whole network, secondary from effects to the stimulated target. The previous cortical stimulation demonstrated changes between the stimulated site and additional network nodes but could not establish network-wide changes (Eldaief et al., 2011).

Here we explore whether stimulation of a network node is spatially specific and can spread beyond stimulated connections to affect distributed network activity. We examined the topography of network modulation by stimulating the right cerebellar node of the default network with intermittent theta-burst stimulation (iTBS) TMS (Fig. 1) and compared the changes in network connectivity to the changes resulting from cerebellar midline (vermis) stimulation and sham stimulation within the same healthy participants. Right lateral cerebellar stimulation was localized with functional connectivity before stimulation, midline stimulation targeted lobule VII of the cerebellar vermis, and sham stimulation was delivered using a specially designed sham coil that replicates the perception of active TMS. Nine participants were scanned using resting-state imaging in three separate experimental sessions during which they received neuronavigated TMS to the lateral cerebellum, the midline cerebellum, or sham stimulation and thereafter immediately returned to the MRI to assess changes in their resting-state connectivity patterns.

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