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Bridging the Gap Between Functional andAnatomical Features of Cortico-Cerebellar Circuits
Using Meta-Analytic Connectivity Modeling
Joshua H. Balsters,1,2 Angela R. Laird,3 Peter T. Fox,4,5 andSimon B. Eickhoff6,7*
1Neural Control of Movement Lab, Department of Health Sciences and Technology,ETH Zurich, Switzerland
2Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland3Department of Physics, Florida International University, Miami, Florida
4Research Imaging Center, University of Texas Health Science Center San Antonio,San Antonio, Texas
5South Texas Veterans Administration Medical Center, San Antonio, Texas6Institute of Neuroscience and Medicine (INM-1), Research Center Julich, Germany
7Institute of Clinical Neuroscience and Medical Psychology, Heinrich-HeineUniversity Dusseldorf, Germany
Abstract: Theories positing that the cerebellum contributes to cognitive as well as motor control aredriven by two sources of information: (1) studies highlighting connections between the cerebellum andboth prefrontal and motor territories, (2) functional neuroimaging studies demonstrating cerebellar activa-tions evoked during the performance of both cognitive and motor tasks. However, almost no studies todate have combined these two sources of information and investigated cortico-cerebellar connectivityduring task performance. Through the use of a novel neuroimaging tool (Meta-Analytic ConnectivityModelling) we demonstrate for the first time that cortico-cerebellar connectivity patterns seen in anatomi-cal studies and resting fMRI are also present during task performance. Consistent with human and non-human primate anatomical studies cerebellar lobules Crus I and II were significantly coactivated withprefrontal and parietal cortices during task performance, whilst lobules HV, HVI, HVIIb, and HVIIIwere significantly coactivated with the pre- and postcentral gyrus. An analysis of the behavioral domainsshowed that these circuits were driven by distinct tasks. Prefrontal-parietal-cerebellar circuits were moreactive during cognitive and emotion tasks whilst motor-cerebellar circuits were more active duringaction execution tasks. These results highlight the separation of prefrontal and motor cortico-cerebellarloops during task performance, and further demonstrate that activity within these circuits relates to dis-tinct functions. Hum Brain Mapp 00:000000, 2013. VC 2013 Wiley Periodicals, Inc.
Key words: cerebellum; meta-analytic connectivity modeling; cognition
Additional Supporting Information may be found in the onlineversion of this article.
*Correspondence to: Simon B. Eickhoff, Institut fur Neurowissen-schaften und Medizin (INM-1), Forschungszentrum Julich GmbH,D-52425 Julich, Germany. E-mail: S.Eickhoff@fz-juelich.de
Received for publication 8 February 2013; Revised 29 July 2013;Accepted 31 July 2013.
DOI 10.1002/hbm.22392Published online 00 Month 2013 in Wiley Online Library(wileyonlinelibrary.com).
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VC 2013 Wiley Periodicals, Inc.
A number of authors have suggested that in order tounderstand the functional properties of a brain region onemust understand its anatomical features and connections[Crick and Koch, 2005; Eickhoff and Grefkes, 2011; Pas-singham et al., 2002]. A great deal is known about theintrinsic microstructure of the cerebellum [Eccles et al.,1967], and a large number of studies have mapped cortico-pontine and cortico-cerebellar connections in humans andnon-human primates [see Ramnani, 2011; Strick et al., 2009for review]. Theories of cortico-cerebellar informationprocessing have been in a large part driven by our under-standing of cortico-cerebellar connectivity. Studies in bothhumans [Buckner et al., 2011; Habas et al., 2009; Krienenand Buckner, 2009; OReilly et al., 2010; Ramnani et al.,2006] and non-human primates [Kelly and Strick, 2003;Middleton and Strick, 2000, 2001; Schmahmann and Pan-dya, 1997] have repeatedly demonstrated that the cerebel-lum receives inputs from a wide range of corticalterritories including (but not restricted to) the premotorand primary motor cortices, medial and dorsal prefrontalcortex, and parietal cortex. Studies in nonhuman primateshave also suggested that prefrontal and motor cortico-cerebellar circuits are completely independent of oneanother and do not exchange information at any pointwithin the loop except for within the frontal lobe. Kellyand Strick  showed in non-human primates that thearm area of the primary motor cortex projected to cerebel-lar lobules HV, HVI, HVIIb, and HVIII, whilst tracer labelinjected into the dorsal bank of the sulcus principalis(putatively Walkers Area 46) terminated in cerebellarlobules Crus I and Crus II. These same connections havebeen shown in humans using resting state fMRI [Buckneret al., 2011; Habas et al., 2009; Krienen and Buckner, 2009;OReilly et al., 2010]. Given that the cerebellum receivesinputs from prefrontal and parietal regions that are knownto process abstract information [Badre and DEsposito,2009], and that this information does not integrate withmotor cortico-cerebellar circuits, it would suggest that thecerebellum is not solely processing motor information.However, in order to further develop theories of cortico-cerebellar connectivity it is necessary to corroborate thesefindings with task-based information.
Along with studies of anatomical and functional con-nectivity, task-based functional neuroimaging studieshave provided a wealth of evidence suggesting that thecerebellum is involved in processing both motor and non-motor information [see Stoodley, 2012 for review]. Petac-chi et al., , Moulton et al. , and Stoodley andSchmahmann  have all conducted meta-analysesinvestigating task-dependent cerebellar processing. WhilstPetacchi et al.  and Moulton et al.,  focusedon auditory and pain processing respectively, Stoodleyand Schmahmann  investigated cerebellar process-ing during a variety of tasks ranging from cognitive tomotor to emotion. They found that cerebellar lobules
Crus I and II were active in studies investigating execu-tive function, working memory, and language tasks,whilst motor control tasks consistently activated cerebellarlobules HV, HVI, and HVIII. This work thus providesfurther evidence that distinct regions of the cerebellumprocess distinct forms of information, both motor andassociative. Although these findings are in keeping withcortico-cerebellar anatomy (i.e., cerebellar lobules inter-connected with prefrontal cortex are active during asso-ciative tasks) it is essential to investigate cortico-cerebellarconnectivity during task performance in order to ascertainthe roles of cortico-cerebellar circuits in cognitive andmotor control.
This study uses a novel neuroimaging tool [Meta-Ana-lytic Connectivity Modelling (MACM)] to integrate con-nectivity information with behavioral information and assuch extend our understanding of cortico-cerebellar infor-mation processing. MACM assesses brain-wise co-activa-tion patterns of an anatomical region across a largenumber of databased neuroimaging results [Eickhoff et al.,2011; Laird et al., 2009a]. First, we identified for each voxelof the seed VOI those experiments in the BrainMap data-base that reported activation at that particular location. Byperforming an Activation Likelihood Estimation (ALE)meta-analysis over these experiments, we can generate awhole brain activation map showing all the brain regionsthat are active when voxels in the seed VOI are active. Dif-ferences in the coactivation patterns of the respective VOIscan be tested by directly contrasting the regional MACMpatterns. Finally, in order to confirm a functional separa-tion between the anatomical VOIs selected in this studywe can assess the behavioral domain and paradigm classmeta-data of experiments associated with the ensuing clus-ters. This manuscript describes the application of MACMto cortico-cerebellar connectivity and the ensuing behav-ioral differences.
Cerebellar lobules of interest were selected based onprevious studies of primate cortico-cerebellar connectivity,specifically Kelly and Strick . Kelly and Strick is the only study performed on non-human primates thattraced anatomical connections from regions of the frontallobe (dorsal bank of the sulcus principalis (Walkers Area46; Walker, 1940) and the hand/arm region of the primarymotor cortex) all the way to the cerebellar cortex. Wedecided to restrict our analyses to cerebellar lobules foundin Kelly and Strick , namely vermal and hemisphericlobules V, VI, Crus I, Crus II, VIIb, VIIIa and HVIIIb(accounting for 86.34% of the cerebellar cortex; Diedrich-sen et al., 2009). There are also additional practical reasonsto restrict our analyses to these lobules. For example,many fMRI studies do not include the very posterior
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lobules of the cerebellum in the field of view, thus thereare fewer studies reporting activations within lobules IXand X. Anterior lobules I-IV can also be contaminated bynon-cerebellar signal originating from the occipital lobesdirectly above them, i.e., the ventral visual cortex [Die-drichsen, 2006]. Cerebellar lobular masks were extractedfrom the probabilistic cerebellar atlas of Diedrichsen et al. and combined to create masks of interest (see Fig.1). For example, the seed mask for the analysis of cerebel-lar motor lobules was created by combining masks ofcerebellar lobules V, VI, VIIb, and VIII (red in Fig. 1). Theatlas of Diedrichsen et al.  conforms to the anatomi-cal landmarks outlined by Larsell and Jansen . Usingthese cerebellar lobules as seeds we investigated differen-ces in task-base