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Aphasiology

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The language of the cerebellum

Kim van Dun, Mario Manto & Peter Mariën

To cite this article: Kim van Dun, Mario Manto & Peter Mariën (2016) The language of thecerebellum, Aphasiology, 30:12, 1378-1398, DOI: 10.1080/02687038.2015.1132297

To link to this article: http://dx.doi.org/10.1080/02687038.2015.1132297

Published online: 12 Jan 2016.

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The language of the cerebellumKim van Duna, Mario Mantob and Peter Mariëna,c

aClinical and Experimental Neurolinguistics, Vrije Universiteit Brussel, Brussels, Belgium; bUnité d’Étude duMouvement, FNRS Neurologie, ULB Erasme, Brussels, Belgium; cDepartment of Neurology and MemoryClinic, ZNA Middelheim, Antwerp, Belgium

ABSTRACTBackground: During the past three decades neuroanatomical, neu-roimaging, and clinical studies have substantially altered the viewon the role of the cerebellum as a sole coordinator of sensorimotorfunction. Currently, the cerebellum is believed to be also cruciallyinvolved in cognitive, affective, and behavioural functioning.Aims: This paper aims to summarise a number of critical insightsfrom different research areas (anatomy, functional imaging, clinicalpractice) that provide evidence for a role of the cerebellum inmotor speech and nonmotor language processing.Main contribution: By means of identifying a dense network ofcrossed reciprocal connections between the cerebellum and thesupratentorial association areas, neuroanatomical studies pro-vided a robust basis for the development of new insights in themodulatory role of the cerebellum in neurocognition, includingnonmotor language processing. A topological distinction wasestablished between the “motor” cerebellum, projecting to thecortical motor areas, and the “cognitive/affective” cerebellum,connected with the cortical and limbic association areas.Neuroimaging studies demonstrated cerebellar involvement inseveral different language tasks, even after controlling formotor aspects. In addition, several clinical studies identified avariety of nonmotor linguistic deficits after cerebellar damage,implying a prominent role for the cerebellum in these linguisticprocesses. Functional neuroimaging confirmed the functionalimpact of cerebellar lesions on remote, structurally intact corticalregions via crossed cerebello-cerebral diaschisis.Conclusion: Evidence from neuroanatomical, neuroimaging, andclinical studies suggests a strongly lateralised involvement of thecerebellum in a broad spectrum of nonmotor language functionsthrough crossed cerebello-cerebral connectivity. It is argued thatthe cerebellum is involved in language in a similar manner as it isinvolved in motor functions: through monitoring/coordinatingcortical functions.

ARTICLE HISTORYReceived 2 April 2015Accepted 12 December 2015

KEYWORDSCerebellum; language;diaschisis; Schmahmann’ssyndrome; timinghypothesis; sequencinghypothesis

Introduction

For centuries, the role of the cerebellum was considered to consist of pure sensorimotorcontrol (Manto & Mariën, 2015). In the last few decades, however, neuroanatomical,

CONTACT Peter Mariën peter.marien5@telenet.be

APHASIOLOGY, 2016VOL. 30, NO. 12, 1378–1398http://dx.doi.org/10.1080/02687038.2015.1132297

© 2016 Taylor & Francis

neuroimaging, and clinical studies have changed this view substantially. The cerebellumis now believed to play a prominent role in cognitive, affective, and behavioural func-tions, including language (De Smet, Paquier, Verhoeven, & Mariën, 2013; Mariën et al.,2014). In this paper, the rapidly growing evidence derived from a number of neuroana-tomical, neuroimaging, and clinical studies is summarised to demonstrate crucial invol-vement of the cerebellum in a wide variety of nonmotor linguistic processes. In addition,current hypotheses about the possible underlying pathophysiological and cognitivemechanisms will be briefly discussed.

Evidence for a role for the cerebellum in language

Anatomical

Neuroanatomically, the cerebellum is not only densely interconnected with the supra-tentorial motor areas, but also with the paralimbic and association cortices throughreciprocal crossed cerebello-cerebral pathways. The cerebellum receives input fromthe cerebral cortical regions via cortico-ponto-cerebellar projections, while feedback isprovided via cerebello-thalamo-cortical projections (Mariën et al., 2014). Histologicaltract tracing studies in monkeys have shown that these feedforward and feedbackprojections form closed loops: a cerebellar area projects back to the cortical areas fromwhich it receives input (Strick, Dum, & Fiez, 2009) (Figure 1).

In addition, neuroanatomical and neurophysiological studies have identified atopological distinction between a “motor” and a “cognitive/affective” cerebellum.Motor-related cortices project primarily to the contralateral anterior cerebellar lobe(lobules I–V) –extending into medial lobule VI, and to lobule VIII via the caudal halfof the pons. Prefrontal, parietal, and temporal association areas project to theposterior cerebellar lobe (Crus I, Crus II, lobule VI/VII/IX) via the mediorostral(prefrontal areas) and dorso- and ventrolateral pons (posterior cerebral hemi-spheres) (Habas et al., 2009; Keren-Happuch, Chen, Ho, & Desmond, 2014; Mariënet al., 2014; Stoodley & Schmahmann, 2010). The affective processes are believed tobe primarily situated in the cerebellar posterior vermis (De Smet et al., 2013;Stoodley & Schmahmann, 2009, 2010) (Figure 2). This topographical division ofthe human cerebellum is also supported by separate olivo-cerebellar connections.While cutaneo-kinesthetic information is provided to the cerebellum via spinocer-ebellar and trigeminocerebellar tracts (with the medial and dorsal accessory olivarynuclei projecting on the sensorimotor cerebellum (lobules I–V, VI, VIII)), the princi-pal olivary nucleus (with little or no spinal cord input) is connected with lobule VIIand the dentate nucleus (DN), and to a smaller degree with lobule VI (Stoodley &Schmahmann, 2010). A similar topographic division between motor and nonmotorareas can also be found in the dentate nuclei, the thalamus, and the pons, theareas involved in the reciprocal cerebello-cerebral loops (see Figure 1). Since mostof the output and input of the cerebellum is regulated by the DN, a divisionbetween a motor and a nonmotor area is also found in the DN (Habas, van Dun,& Mariën, 2015). Projections to and from the motor areas pass through the dorsalpart of the DN, while the projections from the associative cortices pass through the

APHASIOLOGY 1379

Figure 1. (A) Diagram depicting the cerebello-cerebral connectivity network underlying cognitiveand affective processes. The feedback or efferent loop originates from the deep nuclei of thecerebellum that project to the motor (grey arrows) and nonmotor (blue arrows) nuclei of thethalamus. In turn, the motor nuclei of the thalamus project to motor and premotor cortices (greyarrows) but also to nonmotor association cortices (blue arrows). The nonmotor nuclei of the thalamusproject only to association cortices (blue arrows). After Schmahmann and Pandya (1997). Adaptedfrom Mariën et al. (2013). (B) Topographic distribution of motor-related cortices and associationcortex feedforward or afferent projections to the cerebellum. Both motor corticopontine projectionsand association cortex projections are somatotopically organised in the pons. See also Stoodley andSchmahmann (2010). Adapted from Grimaldi and Manto (2012).

Figure 2. Simplified representation of the dichotomy of the cerebellum in a motor (anterior) and acognitive/affective (posterior/vermis) cerebellum. Adapted from Manto and Mariën (2015).

1380 K. VAN DUN ET AL.

ventral part of the DN (Schlerf, Wiestler, Verstynen, & Diedrichsen, 2014; Stricket al., 2009).

From an evolutionary point of view, the larger size of the DN in humans than inprimates is considered the result of expansion of the ventrolateral “nonmotor” part ofthe human DN (Matano, 2001). Enlargement of the DN might reflect the increasedimportance of nonmotor functions in humans (Strick et al., 2009), especially since itsdevelopment during evolution coincided with the expansion of the prefrontal cortex(Middleton & Strick, 1994, 2001). Leiner, Leiner, and Dow (1986) suggested that theparallel expansion of the ventral DN and the frontal cortical areas, which are intrinsicallyimplicated in cognitive functioning, implies involvement of the cerebellum in cognitiveand linguistic processes as well (Leiner et al., 1986). This hypothesis is firmly endorsed bycurrent insights in the neuroanatomical projections from the ventral DN to the prefron-tal cortex.

Functional imaging (see Table 1 for a summary of the cited studies)

Positron emission tomography (PET)In 1988 and 1989, Petersen et al. identified right cerebellar activation in language taskexperiments with positron emission tomography (PET), a technique to measure brainactivity. In their study, the authors used three conditions: first, single words werepresented both aurally and visually to 17 right-handed healthy subjects without anyaction required (sensory task), then they asked these subjects to repeat the presentedword (output task), and finally they had to perform a noun–verb association task(association task) in which an auditory presented noun had to be silently associatedwith a semantically related verb. Activation of the right lateral inferior cerebellum wasfound, specifically in the noun–verb association task. Referring to the anatomical paperof Leiner et al. (1986), they speculated that this activation rather had a “cognitive” rolethan a motor or a sensory one (Petersen, Fox, Posner, Mintun, & Raichle, 1989). Since thisstudy, a large number of experimental and clinical neuroimaging studies have confirmedconsistent involvement of the right posterior cerebellum in silent word generation tasks(e.g., Grabowski et al., 1996; Martin, Haxby, Lalonde, Wiggs, & Ungerleider, 1995;Papathanassiou et al., 2000).

Functional magnetic resonance imaging (FMRI)An activation-likelihood estimate (ALE) meta-analysis performed by Stoodley andSchmahmann (2009) included 11 functional magnetic resonance imaging (fMRI) studies(performed between 1998 and 2006) investigating language-specific activations, con-trolled for motor activation. Several different language tasks were used and contrastedwith various motor tasks to isolate specific language functions such as phonological andsemantic processing, and word generation. For all language tasks, the strongest peaks inthe analysis were lateralised in lobule VI, Crus I/II, and midline lobule VII of the rightcerebellum. Only a small lateral cluster was found in left-hemisphere lobule VI (Stoodley& Schmahmann, 2009). A more recent meta-analysis performed by Keren-Happuch et al.(2014) confirmed the activation of the right lateral posterior cerebellum during languagetasks. This study specifically targeted cerebellar activation clusters. Four studies wereincluded in addition to the meta-analysis performed by Stoodley and Schmahmann

APHASIOLOGY 1381

Table1.

Overview

ofcitedimagingstud

ies.

Functio

nalimaging

Type

ofimaging

Stud

yParticipants

Tasks

Cerebellaractivations

PET

Petersen

etal.(1989)

17R(11F,6

M)

Sensorytask

(fixatio

npo

int)

Outpu

ttask

(passive

words)

Associationtask

(repeatwords)

Non

eSuperio

rAn

terio

rCB

(L+R)

Inferio

rLateralC

B(R)/PosteriorCB

(L+R)

Martin

etal.(1995)

12R(3F,9M

)Co

lour

wordgeneratio

n(reading

alou

d)Verb

generatio

n(reading

alou

d)Non

eLateralC

B(R)

Grabowskie

tal.(1996)

18R

Outpu

ttask

(passive

words)

Associationtask

(repeatwords)

Inferio

rLateralC

B(R

+L)

Papathanassio

uet

al.(2000)

8R(M

)Passivestorylistening

(rest)

Covertverb

generatio

n(rest)

PosteriorCB

(R>L)

Anterio

rCB

(R+L)/Posterio

rCB

(R)

fMRI

Stoodley

andSchm

ahmann

(2009)

Meta-analysisof

11articles

(ALE-m

etho

d)Severald

ifferentlang

uage

tasks

Lobu

leVI—Crus

I(R)/CrusI-II—

lobu

leVIIAt(R)/Lobu

leVI

(L)

Keren-Happuch

etal.(2014)

Meta-analysisof

15stud

ies

(ALE-m

etho

d)Expressive

lang

uage

tasks

Receptivelang

uage

tasks

Lobu

leVI—Midlobu

leVIII—

Crus

I(R)/CrusI(R+L)/Crus

II(R

+L)

Crus

I(R)/Lob

uleVI

(L)

Hubrich-Ungureanu

etal.

(2002)

1R(F),1L

(F)

Covertph

onolog

ical

verbalfluency(rest)

R:CB

(R)

L:CB

(L)

SPECT

Stud

yPatients

Deficit(s)

Lesion

site

Hypop

erfusion

Crossedcerebellardiaschisis

Abeet

al.(1997)

15(6F,9M

)Broca’sAp

hasia

Spared

base

offron

talg

yrus

Base

offron

talg

yrus

Non

eCB

R<L

Mariën,

Pickut,

Engelborghs,Martin,&

DeDeyn(2001)

83yRM

AoS

Phon

olog

icalagraph

iaLanterio

rinsula/adjacent

fron

talo

percular

cortex

CBR<L

Crossedcerebello-cerebral

diaschisis

Mariënet

al.(1996)

73yRM

Luria’sdynamicaphasia

RSCA

Parieto-occipitalregion(R

+L)/

Fron

to-parietalregion(L)

Zettin

etal.(1997)

46yRM

Expressive

agrammatism

RCB

haem

atom

aFron

to-tem

poralcortex(L)/Basal

gang

lia(L)/Thalam

us(L)

Mariënet

al.(2009)

58yRM

Mild

transcorticalsensoryaphasia/Visual

dyslexia/surface

dysgraph

iaRSCAischem

icinfarctio

nMedialfrontallobe

(L)

Baillieux

etal.(2010)

18R(6F,12M)

Attention(72%

)Executive(50%

)Mem

ory(50%

)Behaviou

ral/affective(50%

)

RCB

(vascular:3PICA

,3SCA;

tumou

r:2)

LCB

(vascular:4PICA

,1SCA;

tumou

r:1)

BilateralC

B(vascular:1SCA)

Verm

is(3)

Fron

tal(8/13)

Parietal(2/13)

DeSm

etet

al.(2011)

74yRM

Ataxicdysarthria/dynam

icaphasia/

anom

ia/apraxicagraph

iaRCB

haem

orrhage

Posteriorparietal(L)

Motor/premotor

areas(L)

86yRF

Ataxicdysarthria/apraxicagraph

ia/m

ildattentionprob

lems

R>LCB

ischem

iclesion

sOld

Rtempo

ro-parietal

ischem

icinfarctio

n

Parietallob

e(R)

Motor/premotor

areas(R)

76yRM

Apraxicagraph

ia/frontalprob

lem

solving/mentalfl

exibility

RPICA

infarctio

nOld

Rpo

steriorparietal

ischem

icinfarctio

n

Lateralp

refron

tallob

e(L

+R)

Inferio

rlateralfrontallobe

(L+R)

Inferiormedialfrontallobe

(L+R)

PATIEN

TS:R

:right-handed;

L:left-handed;

F:female;

M:m

ale;

y:years;OTH

ERCO

LUMNS:

R:rig

ht;L:left;CB

:cerebellum;S

CA:sup

eriorcerebellarartery;P

ICA:

posteriorinferio

rcerebellar

artery;SCA

6:SpinocerebellarAtaxia6;

ALE:activation-likelihoodestim

ation.

1382 K. VAN DUN ET AL.

(2009), expanding the range from 2006 to 2010 (Keren-Happuch et al., 2014). Thus,involvement of the right posterior lateral cerebellar hemisphere in language via crossedanatomical connections with the language-dominant left frontal, parietal, and temporalassociation areas was confirmed by functional neuroimaging.

The fMRI study performed by Hubrich-Ungureanu, Kaemmerer, Henn, and Braus(2002) also demonstrated crossed cerebello-cerebral activations subserved by crossedanatomical tracts between the supratentorial association cortices and the cerebellum. Aright-handed subject with typical left hemisphere language dominance and a left-handed subject with atypical right hemisphere language dominance were asked tosilently perform a verbal fluency task in the scanner. In addition to activation of theleft fronto-parietal cortex involvement, the right cerebellar hemisphere was found in theright-handed subject, while in the left-handed subject, the left cerebellar hemispherewas co-activated with the right fronto-parieto-temporal cortex (Hubrich-Ungureanuet al., 2002). This study not only confirmed involvement of the cerebellum in languagetasks, but also showed a clear lateralisation of cerebellar involvement contralateral to thelanguage-dominant left or right cerebral hemisphere.

Single photon emission computerised tomography (SPECT)Crossed (cerebro-)cerebellar diaschisis. Evidence for a pattern of crossed activationshas also been provided by SPECT studies which measure cerebral blood perfusion. Baron(1980) described the phenomenon of crossed cerebellar diaschisis, denoting the distantfunctional impact of a supratentorial lesion on the contralateral cerebellar hemisphere.Crossed cerebellar diaschisis associated with language deficits was investigated by Abe,Ukita, Yorifuji, and Yanagihara (1997). They performed a group study with MRI andSPECT in 30 patients with chronic Broca’s aphasia after cerebral damage. It was shownthat infarcts affecting the lower part of the left frontal gyrus were associated withcrossed cerebellar diaschisis, implying functional and/or anatomical connections of thissupratentorial region with the right cerebellar hemisphere. Interestingly, patients withcrossed cerebellar diaschisis presented with classical Broca’s aphasia, while patientswithout damage to the lower left frontal gyrus mainly presented with word-findingdifficulties without additional more complex language impairments (Abe et al., 1997). Inaddition, several case studies using SPECT imaging in patients with Apraxia of Speech(AoS) after left insular infarctions, provided support for a close interconnection betweenthe language-dominant left frontal regions, and the right cerebellum (e.g., Mariën,Pickut, et al., 2001). After an isolated infarction in the precentral gyrus of the lan-guage-dominant insula, directly anterior to the central insular sulcus, an 83-year-oldright-handed patient presented with severe AoS and phonological agraphia. A Tc-99m-ECD SPECT scan nine days after admission revealed a hypoperfusion in the left inferiorfrontal gyrus and precentral gyrus, and in the right cerebellar hemisphere (Mariën,Pickut, et al., 2001).

Crossed cerebello-cerebral diaschisis. The reversed phenomenon in which (focal)cerebellar damage exerts a distant functional effect at the supratentorial level is calledcrossed cerebello-cerebral diaschisis. Decreased cerebral blood flow in the cerebralhemisphere contralateral to the lesioned cerebellar hemisphere is an indirect measureof function often found in the anatomoclinically suspected supratentorial regions

APHASIOLOGY 1383

subserving linguistic and cognitive functions (Baillieux et al., 2010; De Smet,Engelborghs, Paquier, De Deyn, & Mariën, 2011; Mariën et al., 1996, 2007; Zettin et al.,1997).

Clinical evidence (see Table 2 for a summary of the cited studies)

Clinically, several different types of motor and nonmotor language deficits have beenreported after cerebellar damage, ranging from pure motor speech disorders to high-level metalinguistic disturbances.

Motor speech productionAtaxic dysarthria is a typical cerebellar motor speech disorder, mainly characterisedby distorted articulation and prosody (Spencer & Slocomb, 2007). Traditionally, ataxicdysarthria is considered a disorder of motor execution. However, recent studies havemodified this view to also include disruption of motor speech programming inaddition to a dysfunctional execution of speech (Mariën & Verhoeven, 2007;Spencer & Slocomb, 2007). This was based on some typical characteristics of ataxicdysarthria which are more compatible with a programming/planning disorder thanwith an execution one (Spencer & Slocomb, 2007). Moreover, ataxic dysarthria seemsto share some overt semiological characteristics with AoS, a typical planning andprogramming disorder, which has led to the hypothesis that both disorders aresubserved by related pathophysiological mechanisms (Mariën et al., 2006). Mariënet al. (2006) and Mariën and Verhoeven (2007) observed a significant correlationbetween the perfusional deficits in the right cerebellum and the remission of AoSsymptoms in two patients with a subtype of AoS, suggesting an involvement of thecerebellum in the planning and programming of speech.

Verbal fluency and language dynamicsDisruption of verbal fluency and language dynamics has repeatedly been observed inpatients with focal and degenerative cerebellar lesions (Leggio, Silveri, Petrosini, &Molinari, 2000; Peterburs, Bellebaum, Koch, Schwarz, & Daum, 2010; Schweizer,Alexander, Susan Gillingham, Cusimano, & Stuss, 2010), with phonological fluencymore prominently affected than semantic fluency. Although Hubrich-Ungureanu et al.(2002) confirmed lateralisation of cerebellar involvement in a (silent) phonologicalfluency task and Schweizer et al. (2010) observed a clear lateralisation effect, anumber of other studies contradict unilateral involvement of the cerebellum in verbalfluency tasks (Cook, Murdoch, Cahill, & Whelan, 2004; Leggio et al., 2000). However,despite some conflicting results with respect to laterality, a consensus exists withregard to the role for the cerebellum in verbal fluency and lexical retrieval (Mariënet al., 2014).

Mariën et al. (1996) described a patient who, after an ischemic infarction in thevascular territory of the right superior cerebellar artery (SCA), presented with aphasicsymptoms corresponding to Luria’s dynamic aphasia (characterised by severelyreduced, adynamic, fragmented self-generated speech despite normal confrontationalnaming and phonological skills). A review by Mariën, Engelborghs, Fabbro, and DeDeyn (2001) disclosed several additional cases in which language dynamics were

1384 K. VAN DUN ET AL.

Table2.

Overview

ofcitedcase

repo

rts.

Clinicalevidence

Lang

uage

deficit

Stud

yPatient

Deficits

Lesion

site

Imaging

Motor

speech

prod

uctio

nMariënand

Verhoeven(2007)

53yRF

FAS

Fron

to-parietal

stroke

SPECT(33days

poststroke):

hypo

perfusionin

CB(R)

61yRM

Cond

uctio

n-likeaphasia/FA

SLbasalg

anglia

haem

orrhageinto

Lparietotempo

ral

region

SPECT(1

mon

thpo

ststroke):

hypo

perfusionin

CB(R)

Spencerand

Slocom

b(2007)

20stud

ies(health

yparticipants)19

stud

ies

(dysarthric

patients)

Non

eAtaxicdysarthria

Non

eCerebellar

lesion

sfM

RI/PET/ERP

fMRI/PET

•Bilateralsup

eriorCB

:speechmotor

control

•RCB

:plann

ingandprocessing

ofspeech

Verbalfluency

Legg

ioet

al.(2000)

25patients(cerebellar

disease)

14healthycontrols

Phon

emicfluency:CB

patients<

controls

Semantic

fluency:CB

patients~

controls

Focalo

rdegenerativeCB

disease(L:n

=13;R

:n=6;

idiopathic:

n=6)

Schw

eizeret

al.

(2010)

22patients(chron

iccerebellar

lesion

s)30

healthycontrols

Phon

emicfluency:RCB

patients<L

CBpatients~controls

Semantic

fluency:RCB

patients<

controls

LCB

:n=12

RCB

:n=10

Cook

etal.(2004)*

5patients(vascularcerebellar

lesion

s)Ph

onem

icfluency/sentence

constructio

n/worddefinitio

ns/

multip

ledefinitio

ns/figu

rative

lang

uage/w

ordassociations/sem

antic

absurdities/synon

yms/

antonyms

LCB

(ischem

icor

haem

orrhagic)

Mariënet

al.

(1996)*

73yRM

Luria’sdynamicaphasia

RSCA

SPECT(30days

poststroke):

hypo

perfusionin

Parieto-occipitalregion

(R+L)

Fron

to-parietalregion(L)

Riva

(1998)

4y2m

FMutism–>

redu

cedspon

taneou

sspeech/aph

onic/aprosod

ic/sequential

mem

ory

Viralcerebellitis

Gasparin

ietal.

(1999)*

51yRM

Agrammatism/dysprosod

yRCB

infarctio

nSPECT:hypo

perfusionin

RCB (C

ontin

ued)

APHASIOLOGY 1385

Table2.

(Con

tinued).

Clinicalevidence

Lang

uage

deficit

Stud

yPatient

Deficits

Lesion

site

Imaging

Fabb

roet

al.

(2000)*

21yRM

Syntax/synon

yms/attributegeneratio

nArachn

oidalcystin

PF28yRF

Syno

nym/arithm

etics/writingto

dictation

Hem

angiob

lastom

ain

PF48yRM

Dysarthria/fluency/

prop

osition

ing/

lexicalaccess/morph

olog

y/syntax/

semantics/behaviou

ral/w

ritingto

dictation

CBastrocytom

ain

verm

is

59yF

Grammar/arithm

etics/

reading/syntax/

writingto

dictation

LCB

astrocytom

a

Riva

andGiorgi

(2000)

26patients

Mutism

=>dysarthriaORAff

ective/

social

behaviou

rald

isturbances

RCB

astrocytom

a(n

=7)

LCB

astrocytom

a(n

=8)

CBverm

ismedulloblastoma

(n=11)

Grammatical/Syntactical

processing

Silverie

tal.(1994)

67yRM

Expressive

agrammatism

RCB

infarct

SPECT(5

weeks

poststroke):

hypo

perfusionin:Cerebralh

emisph

ere(L)

Zettin

etal.(1997)

46yRM

Expressive

agrammatism

RCB

haem

atom

aSPECT(4

weeks

poststroke):

hypo

perfusionin

Fron

to-tem

poralcortex

(L)Basalg

anglia

(L)Thalam

us(L)

Ackerm

annet

al.

(1999)

9(3F,6M

)Ataxia/receptiveagrammatism

Degenerative

cerebellaratroph

y

Mariënet

al.

(1996)*

73yRM

Luria’sdynamicaphasia

RSCA

SPECT(30days

poststroke):

hypo

perfusionin

Parieto-occipitalregion

(R+L)

Fron

to-parietalregion(L)

Gasparin

ietal.

(1999)*

51yRM

Agrammatism/dysprosod

yRCB

infarctio

nSPECT:hypo

perfusionin

RCB (C

ontin

ued)

1386 K. VAN DUN ET AL.

Table2.

(Con

tinued).

Clinicalevidence

Lang

uage

deficit

Stud

yPatient

Deficits

Lesion

site

Imaging

Justus

(2004)

16patients16

controls

Grammaticalmorph

olog

yRCB

(n=3)

LCB

(n=3)

MidlineCB

(n=1)

BilateralC

B(n

=9)

Adam

aszeket

al.

(2012)

8Rpatients(1F,7M

)8R

controls(2F,6M

)Syntactic

processing

RCB

(n=2)

LCB

(n=6)

Reading

Morettiet

al.

(2002)

10Rpatients(4F,6M

)10Rcontrols(5F,5M

)Reading

Verm

ian/

paraverm

iantumou

r

Mariënet

al.

(2009)*

58yRM

Mild

transcorticalsensoryaphasia/

Visualdyslexia/surface

dysgraph

iaRSCAischem

icinfarctio

nSPECT(5

weeks

poststroke):

hypo

perfusionin

CB(R)Medialfrontal

lobe

(L)

Writing

Silverie

tal.(1997)

67yRM

Spatiald

ysgraphia

Cerebellaratroph

ySilveri,Misciagna,

Legg

io,and

Molinari(1999)

26yRF

Spatiald

ysgraphia

CBhaem

orrhage

(vermis+R>L

hemisph

ere)

Mariënet

al.

(2007)

72yRM

Apraxicagraph

iaRCB

haem

orrhage

SPECT(1

and6mon

thspo

ststroke):

hypo

perfusionin

CB(R)Medial/lateral

prefrontalarea

(L)

DeSm

etet

al.

(2011)

74yRM

Ataxicdysarthria/dynam

icaphasia/

anom

ia/apraxicagraph

iaRCB

haem

orrhage

SPECT(1

and6mon

thspo

ststroke):

hypo

perfusionin

Posteriorparietal(L)

Motor/premotor

areas(L)

86yRF

Ataxicdysarthria/apraxicagraph

ia/

mild

attentionprob

lems

R>LCB

ischem

iclesion

sOld

Rtempo

ro-parietal

ischem

icinfarctio

n

SPECT(1

and6mon

thspo

ststroke):

hypo

perfusionin

Parietallob

e(R)Motor/

prem

otor

areas(R)

76yRM

Apraxicagraph

ia/frontalprob

lem

solving/mentalfl

exibility

RPICA

infarctio

nOld

Rpo

steriorparietal

ischem

icinfarctio

n

SPECT(2

weeks

poststroke):

hypo

perfusionin

Lateralp

refron

tallob

e(L

+R)

Inferio

rlateralfrontallobe

(L+R)

Inferio

rmedialfrontallobe

(L+R)

Mariënet

al.

(2009)*

58yRM

Mild

transcorticalsensoryaphasia/

Visualdyslexia/surface

dysgraph

iaRSCAischem

icinfarctio

nSPECT(5

weeks

poststroke):

hypo

perfusionin

CB(R)Medialfrontal

lobe

(L)

(Con

tinued)

APHASIOLOGY 1387

Table2.

(Con

tinued).

Clinicalevidence

Lang

uage

deficit

Stud

yPatient

Deficits

Lesion

site

Imaging

Fabb

roet

al.

(2000)*

28yRF

Syno

nym/arithm

etics/writingto

dictation

Hem

angiob

lastom

ain

PF

48yRM

Dysarthria/fluency/

prop

osition

ing/

lexicalaccess/morph

olog

y/syntax/

semantics/behaviou

ral/w

ritingto

dictation

CBastrocytom

ain

verm

is

59yF

Grammar/arithm

etics/

reading/syntax/

writingto

dictation

LCB

astrocytom

a

Fabb

ro(2004)

26yRM

Writingto

dictation

LCB

ischem

icinfarctio

n

30yRM

Writingto

dictation

LCB

ischem

icinfarctio

n

VanGaalenet

al.

(2014)

29patients

Writingto

dictation

SCA6

Metalingu

istic

skills

Cook

etal.(2004)*

5patients(vascularcerebellar

lesion

s)Ph

onem

icfluency/sentence

constructio

n/worddefinitio

ns/

multip

ledefinitio

ns/figu

rative

lang

uage/w

ordassociations/sem

antic

absurdities/synon

yms/

antonyms

LCB

(ischem

icor

haem

orrhagic)

Whelanand

Murdo

ch(2005)

2patients

16healthycontrols

Recreatin

gsentences/antonyms/

definitio

n/multip

ledefinitio

nsLCB

vascular

infarct

Murdo

chand

Whelan(2007)

10Rpatients(2F,8M

)10Rcontrols

Phon

emicfluency/sentence

form

ulation/lexical-sem

antic

manipulation

LCB

(ischem

icor

haem

orrhagic)

PATIEN

TS:R

:right-handed;

L:left-handed;

F:female;M:m

ale;y:years;m:m

onths;OTH

ERCO

LUMNS:R:

right;L:left;CB

:cerebellum;SCA

:sup

eriorcerebellarartery;P

ICA:

posteriorinferio

rcerebellarartery;SCA

6:SpinoC

erebellarAtaxia6.

*Stud

ieswhich

occurmorethan

once

inthetabledu

eto

thesimultaneou

soccurrence

ofdifferentdisordersin

apatient.

1388 K. VAN DUN ET AL.

consistently disturbed after (right) cerebellar damage, resembling transcortical motoraphasia (Fabbro, Moretti, & Bava, 2000; Gasparini et al., 1999; Riva, 1998). Disruptionof language dynamics also characterises the Posterior Fossa Syndrome (PFS), a clinicalcondition consisting of transient cerebellar mutism, cognitive symptoms, and beha-vioural abnormalities that typically occurs in children after posterior fossa tumourresection (Riva & Giorgi, 2000).

Grammatical/syntactical processingGrammatical and syntactic disorders are also associated with cerebellar damage. Bothexpressive (Silveri, Leggio, & Molinari, 1994; Zettin et al., 1997) and receptive agramma-tism (Ackermann, Gräber, Hertrich, & Daum, 1999) have been observed. In most cases,the grammatical disorders are caused by right cerebellar lesions (Gasparini et al., 1999;Mariën, Engelborghs, Pickut, & De Deyn, 2000; Mariën et al., 1996; Silveri et al., 1994;Zettin et al., 1997). However, there are reports of patients with left cerebellar lesions whoalso presented with grammatical and/or syntactic deficits (Adamaszek, Strecker, &Kessler, 2012; Justus, 2004).

ReadingOnly a handful of cases are described in which acquired cerebellar damage leads toreading difficulties (Mariën et al., 2009; Moretti, Bava, Torre, Antonello, & Cazzato, 2002).Moretti et al. (2002) demonstrated that patients with cerebellar lesions made moreerrors at letter- and word level in reading words and sentences, compared to right-handed controls. More recently, Mariën et al. (2009) reported a patient with visualdyslexia after an ischemic infarction in the vascular territory of the right SCA. A quanti-fied SPECT study showed a relative hypoperfusion in the right cerebellar hemisphereand the left medial frontal lobe, which may be caused by a functional disruption of thecerebello-cerebral pathways (Mariën et al., 2009).

WritingIn the last few decades, cerebellar lesions have been frequently associated with writingdisorders. Both peripheral agraphia, a disorder of the coordination, planning, andexecution of writing movements, not attributable to motor or sensory impairments(e.g., spatial dysgraphia, apraxic agraphia) and central agraphia, involving the centralspelling processes, have been reported. Silveri, Misciagna, Leggio, and Molinari (1997,1999) described two patients with spatial dysgraphia after cerebellar damage, andMariën et al. (2007) and De Smet et al. (2011) reported several patients with acquiredapraxic agraphia associated with focal cerebellar damage. Quantified SPECT studies inthe patients with apraxic agraphia consistently showed reduced perfusion in the medialprefrontal regions of the left hemisphere, known to be involved in the planning andexecution of skilled graphomotor actions, and the right cerebellum.

Central agraphia on the other hand is only scarcely reported after cerebellardamage. Mariën et al. (2009) described a patient with surface dysgraphia (togetherwith visual dyslexia) after an ischemic infarction in the vascular territory of the rightSCA. A quantified SPECT study showed a hypoperfusion in the left medial frontal lobe.Other possible cases of central agraphia are difficult to evaluate due to limited

APHASIOLOGY 1389

information about the observed writing disorder (Fabbro, 2004; Fabbro et al., 2000;Van Gaalen et al., 2014).

Metalinguistic skillsSeveral case studies point to an involvement of the left cerebellar hemisphere in higherlevel language and metalinguistic skills. Some patients with primary left cerebellar strokeare known to have difficulties with providing multiple definitions for homophonicwords, recreating sentences, figurative and ambiguous language, word associations,antonym/synonym generation, and interpreting semantic absurdities (Cook et al.,2004; Murdoch & Whelan, 2007; Whelan & Murdoch, 2005). These symptoms are typicallyassociated with right cerebral damage (Kempler, Van Lancker, Marchman, & Bates, 1999).

Possible pathophysiological mechanisms and cognitive theories forcerebellar involvement in language

Several different hypotheses have been put forward to explain the pathophysiologicaland cognitive mechanisms by means of which the cerebellum has a role in linguisticprocesses.

Pathophysiological mechanisms

In 1987, Broich, Hartmann, Biersack, and Horn for the first time described crossedcerebello-cerebral diaschisis after a cerebellar infarction. Their SPECT study showed arelative hypoperfusion in the contralateral left hemisphere in their patient with a rightcerebellar infarction. They hypothesised that crossed perfusional deficits reflect a func-tional depression of the supratentorial areas due to a lack of excitatory stimuli throughthe cerebello-ponto-thalamo-cerebral pathways which connect the cerebellum to sev-eral cerebral association areas crucially implicated in cognitive and affective processing(Broich, Hartmann, Biersack, & Horn, 1987).

Since then, crossed cerebello-cerebral diaschisis has been frequently observed inpatients with speech and language deficits after cerebellar damage (Baillieux et al.,2010; De Smet et al., 2011; Hassid, 1995; Mariën et al., 2000, 1996, 2007; Zettin et al.,1997). For example, Mariën et al. (1996) described a 73-year-old right-handed man withan ischemic infarction in the right superior cerebellum. The patient presented withaphasic symptoms closely resembling Luria’s dynamic aphasia, complicated by receptiveand expressive agrammatism. SPECT findings revealed relative hypoperfusions in theclinically suspected prefrontal regions of the language-dominant hemisphere. Moreover,the pattern of perfusional deficits mirrored linguistic recovery: the prefrontal languageregions regained normal perfusion when remission of the aphasic symptoms wasobserved. This evidence strongly suggests a link between crossed cerebello-cerebraldiaschisis and cerebellar-induced language disturbances (Mariën et al., 2000, 1996).

Cognitive theories

In 1998, Schmahmann and Sherman introduced the concept of cerebellar cognitiveaffective syndrome (CCAS) or Schmahmann’s syndrome (Manto & Mariën, 2015). After

1390 K. VAN DUN ET AL.

screening and testing of 20 patients with isolated cerebellar lesions, they identified acluster of symptoms that could be classified in four categories: (1) executive dysfunc-tions (planning, set-shifting, abstract reasoning, and working memory), (2) visuospatialdeficits (visuospatial organisation and memory), (3) behavioural-affective disturbances(blunting of affect or disinhibited and inappropriate behaviour) and (4) language symp-toms (agrammatism and anomia), (Schmahmann & Sherman, 1998). To explain thecerebellar induced deficits, Schmahmann (1998) introduced the concept of “dysmetriaof thought”, which draws analogies with the motor system. This hypothesis suggests arole for the cerebellum as a modulator of cognitive and affective function that comparesthe intended outcome with the perceived outcome to detect and prevent or correctmismatches. Schmahmann (1998) hypothesised that the cerebellum acts as an oscilla-tion dampener, smoothing out performance of mental operations (Mariën et al., 2014;Schmahmann, 1998).

Due to its architectural homogeneity and its dense interconnections with thesupratentorial association areas, it is frequently stated that the cerebellum contri-butes to both motor and nonmotor activities in a similar manner. Schmahmannreferred to this unique computation as the “universal cerebellar transform” (UCT)(Koziol et al., 2014; Schmahmann, 2000). This phenomenon allows the cerebellum tocompare predictions of “internal models” (= “any neural representation of theexternal world” (Ito, 2008)) with the incoming feedback from the cerebrum, optimis-ing human behaviour and performance. This explanation is in accordance with theconcept of “dysmetria of thought” that Schmahmann introduced in 1998(Schmahmann, 1998) and which implies a “universal cerebellar impairment” (UCI).If the cerebellum is involved in every cortical process in the same way, cerebellardamage should result in a similar kind of disruption of these processes (Koziol et al.,2014). In this context, Schmahmann reported in a number of studies that everydeficit resulting from cerebellar damage can be interpreted as hypometric/dimin-ished or hypermetric/exaggerated behaviours (for an overview, see Koziol et al.,2014). As a result, the theories relating to motor dysfunction and cerebellar diseasewere adapted to account for the observed linguistic deficits after cerebellar damage(Mariën et al., 2014; Strick et al., 2009).

Internal models have been used to explain the ability to perform controlled andskilful movements by creating a prediction of the dynamics of a body part. Thesepredictions help to perform a complex movement in a very precise way withoutconstantly relying on sensory feedback (Ito, 2008). Ito (2008) hypothesised that theseinternal models can be used in the same manner to create and manipulate mentalrepresentations, in association with the prefrontal and the temporo-parietal cortex.These models have also been used to explain the involvement of the cerebellum inlanguage (Mariën et al., 2014). In language studies, the cerebellum is frequentlyregarded as a predictor of future states (as in the “dysmetria of thought” hypothesis(Schmahmann, 1998)) that uses these predictions to optimise cognitive and languagefunctioning by comparing them with the cortical feedback (Mariën et al., 2014).

However, which information the cerebellum uses to form these predictions remains amatter of debate (Leggio & Molinari, 2015). Below, two main hypotheses of the motorliterature are discussed in the context of cognitive and language functions. These two

APHASIOLOGY 1391

theories are frequently cited in studies that found involvement of the cerebellum inlanguage functioning (Mariën et al., 2014).

Timing hypothesisKeele and Ivry (1990) suggested that the cerebellum is responsible for the temporalcomputation of a number of different tasks. This hypothesis was primarily based onobservations of timing deficits in cerebellar patients. Patients with cerebellar disor-ders had trouble judging the velocity of moving visual stimuli and differentiatingbetween two auditory stimuli of different lengths. As a result, Keele and Ivry (1990)proposed a role for the cerebellum in providing temporal information in motorcoordination. According to these authors, the cerebellum times different movementsbut also incorporates cortical input to adjust this timing accordingly, such as inlocomotion. The cerebellum is therefore responsible for the timing of the expectedfeedback and the actual feedback. If an expected feedback comes earlier or laterthan expected, it will be treated as an unexpected event due to the timing coordina-tion of the cerebellum (Gellman, Gibson, & Houk, 1985; Keele & Ivry, 1990). Silveriet al. (1994) and Gasparini et al. (1999) used the timing hypothesis to explain thelinguistic deficits observed after right cerebellar damage in their patients. Theyspeculated that the agrammatism they observed in patients with cerebellar lesionsmight be the result of a delay in the application of syntactic rules and linguisticprocesses (Gasparini et al., 1999). Due to this delay, caused by the damage in thecerebellum, the information held in the verbal working memory decays before all theoperations are performed, resulting in errors (Gasparini et al., 1999; Silveri et al.,1994). As such, the cerebellum times the linguistic operations performed on theinformation held in the verbal working memory.

Sequencing hypothesisAnother explanation of cerebellar involvement in language is provided by thesequencing hypothesis. The cerebellum as a monitor of sequential events has alreadybeen proven in the somatosensory system using expected and unexpected stimuli(Leggio, Chiricozzi, Clausi, Tedesco, & Molinari, 2011). With respect to language, it ishypothesised that the activity of different functional modules, necessary to performlinguistic processes, is synchronised and coordinated by the cerebellum. The cerebel-lum might act as a monitor and supervisor of the sequence in which linguisticprocesses are performed, integrating its activity with the so-called “frontal-lobesystem” (Fabbro et al., 2000). Especially in novel strategies (e.g., used in phonologicalfluency), the cerebellum would play an important role in smoothing and speeding upthe process (Leggio et al., 2011; Mariën et al., 2014).

It is also believed that the cerebellum is responsible for the temporal and sequentialorganisation of both overt and covert speech (Ackermann, 2008). Ackermann, Mathiak,and Ivry (2004) suggested that cognitive deficits observed after cerebellar damage couldbe due to an impairment of the “inner speech”, which can compromise the verbalworking memory (Koziol et al., 2014). The performance on cognitive operations invol-ving a generation of a prearticulatory speech code most likely suffers if this “innerspeech” function is compromised (Ackermann et al., 2004).

1392 K. VAN DUN ET AL.

A lateralised linguistic cerebellum

All suggested cognitive theories strongly rely on the crossed functional cerebello-cere-bral connections, via which the cerebellum exerts its modulatory influence on thecognitive functions subserved by the supratentorial areas. Each of these theories regardthe cerebellum as a coordinator/modulator of supratentorial motor, cognitive, andaffective processes, recognising the cerebellum as a non-specific high-level operationaldevice that provides active support to a variety of functions in a similar manner (Mariënet al., 2014). Since in the vast majority of right-handers (±97%) and in most left-handers(±70%) the left hemisphere is dominant for language (Knecht et al., 2000; Mariën,Paghera, De Deyn, & Vignolo, 2004), it is assumed that the involvement of the cerebel-lum in language functions is strongly lateralised to the right hemisphere, while the leftcerebellar hemisphere primarily contributes to right hemisphere functioning (Mariën,Engelborghs, et al., 2001; Stoodley & Schmahmann, 2009). Several studies have shownthat the configuration of language lateralisation at the supratentorial level is stronglyrelated to a contralateral lateralised language representation at the cerebellar level.Jansen et al. (2005) showed that atypical right-hemisphere language dominance isaccompanied by a left-lateralised cerebellar contribution to language. Additionally,Mendez Orellana et al. (2014) found a significant dependency between language later-alisation in the cerebrum and the cerebellum with an inverse correlation of cerebro-cerebellar lateralisation. This means that the stronger the language lateralisation in thecerebral hemisphere, the stronger the contralateral cerebellar hemisphere is involved inlanguage. Clinically, this is confirmed by a study of Baillieux et al. (2010). They system-atically investigated 18 patients with primary cerebellar lesions by means of an extensiveneuropsychological battery. Although disturbances of attention, executive function, andmemory were most commonly found, their analyses supported the hypothesis of afunctionally lateralised linguistic cerebellum with the right cerebellum being associatedwith logical reasoning and language processing, and the left cerebellum with attentionaland visuo-spatial skills (Baillieux et al., 2010).

Conclusion

Converging evidence from an increasing number of neuroanatomical, neuroimaging, andclinical studies unambiguously shows that the cerebellum plays a cardinal role in a varietyof linguistic processes via a dense network of cerebello-cerebral connections. Thesecrossed connections have led to the concept of a “lateralised linguistic cerebellum” inwhich the right cerebellar hemisphere is involved in left-hemispheric, and the left cere-bellar hemisphere in right-hemispheric functioning (Mariën, Engelborghs, et al., 2001).Many SPECT studies in patients with cerebellar disorders have demonstrated the functionalimpact of a cerebellar lesion on a remote, structurally intact language area, suggestingcrossed cerebello-cerebral diaschisis as the possible pathophysiological mechanism under-lying the observed linguistic deficits.

Due to the architectural homogeneity of the cerebellum, a “UCT” was proposedby Schmahmann (2000), resulting in a “UCI”. According to this hypothesis thecerebellum acts as a coordinator/modulator of both motor and nonmotor (cogni-tive/affective) functions by comparing cortical feedback with “internal models”.

APHASIOLOGY 1393

These models are internal representations/predictions of future states (Mariën et al.,2014). Which information is used to make up these “internal models”, is still amatter of debate. The “dysmetria of thought” theory indicates that the cerebellumtries to keep motor and cognitive processes around a homeostatic baseline, actinglike an oscillation dampener, without specifying which aspects of the processes aremonitored (Schmahmann, 1998). Two factors adapted from the motor literaturehave been discussed in this paper that may hypothetically account for the observedlanguage disturbances: timing and sequencing. Both mechanisms have been dealtwith in the literature to explain the observed language deficits (timing: Silveri et al.,1994; Gasparini et al., 1999; | sequencing: Fabbro et al., 2000; Ackermann et al.,2004). However, future studies are needed to unravel the specific involvement ofthe cerebellum in cognitive functioning, as it is not always clear which languagedeficits are due to a timing deficit, which to a disruption of sequencing, and whichare merely due to disturbed attention control. Hypothetically, it might be arguedthat a timing deficit leads to errors in which not all linguistic operations aresuccessfully completed, such as the use of infinitives instead of a conjugated verbin agrammatism. Due to the delay caused by the timing deficit, as hypothesised bySilveri et al. (1994) and Gasparini et al. (1999), the information temporarily stored inthe working memory system decays before all operations are completed (Gaspariniet al., 1999; Silveri et al., 1994). However, a timing deficit as described by Keele andIvry (1990) and Gellman et al. (1985) could lead to other kinds of errors due to adeficit in timing and coordinating the cortical feedback. This hypothesis merelypredicts a disruption of the incorporation of the cortical feedback due to aninaccurate timing of the expected and the actual input. This could lead to a varietyof linguistic errors. The sequencing hypothesis (Leggio & Molinari, 2015), on theother hand, predicts a deficit in the coordination and monitoring of the sequenceof application of different linguistic operations. According to this hypothesis, repe-titive patterns of temporally or spatially structured serial events are identified andsimulated by the cerebellum. Based on this, the cerebellum generates internalmodels that can be used to make predictions. Disruption of serial pattern detectionand prediction, and processing of anticipation might not only lead to the use ofinfinitives instead of a conjugated verb, but also to wrongfully conjugated verbs.

In the literature on the role of the cerebellum in motor processing, both timing andsequencing deficits have been observed after cerebellar damage (timing: Keele & Ivry,1990; | sequencing: Leggio et al., 2011). It is therefore possible that the cerebellum isinvolved in both mechanisms, resulting in complicated linguistic errors due to bothtiming and sequencing deficits.

In conclusion, it can be stated that the cerebellum contributes in a unique way to themodulation and coordination of a variety of motor and nonmotor (cognitive/affective)processing.

Disclosure statement

No potential conflict of interest was reported by the authors.

1394 K. VAN DUN ET AL.

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