IF THE CEREBRUM GETS ALL OF IT RIGHT, IS THERE SOMETHING LEFT FOR THE CEREBELLUM?

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IF THE CEREBRUM GETS ALL OF IT RIGHT, IS THERE SOMETHING LEFT FOR THE CEREBELLUM?

An FMRI study assessing cerebellar lateralization

Naomi Vanderpoorten

Student number: 01405657

Promotor: Prof. Dr. Guy Vingerhoets Supervisor: Robin Gerrits

A dissertation submitted to Ghent University in partial fulfilment of the requirements for the degree of Master of Science in Theoretical and Experimental Psychology

Academic year: 2018 – 2019

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DANKWOORD

Allereerst wil ik mijn begeleider, Robin Gerrits bedanken voor zijn steun en hulp tijdens het verloop van dit project. Bedankt voor de toegankelijkheid, de tijd en de verhelderende inzichten. Ik kon me geen betere begeleiding voorstellen. Evenzeer wil ik professor Guy Vingerhoets bedanken voor zijn tijd en wegwijs in de wereld van fMRI en situs inversus. Bijkomend wil ik in het bijzonder mijn klasgenoten bedanken voor hun onvoorwaardelijke steun, kritische inzichten en relativerende humor. De wekelijkse meetings en etentjes zal ik altijd koesteren en droegen bij tot de productiviteit die het schrijven van deze masterproef mogelijk maakte. Ik zie deze masterproef als een mooi testament van vijf leerrijke, maar ook heel plezante jaren.

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LIST OF ABBREVIATIONS

AFS: atypical functional segregation LI: lateralization index

rTFS: reversed typical functional segregation SI: situs inversus

SS: situs solitus

TFS: typical functional segregation

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ABSTRACT

Over the years, it has become increasingly apparent that the cerebellum is involved in more than only motor functions. The cerebellum’s involvement in non-motor processes’ was supported by anatomical evidence of cerebro-cerebellar channels, as well as a wide range of clinical and functional research. However, cerebellar lateralization during cognitive tasks is often demonstrated to be reversed compared to cerebral functional asymmetry. We will explore cerebellar lateralization in four known lateralized tasks (word fluency, tool pantomime, spatial attention, and face recognition) in a sample of participants with or without visceral reversal (situs inversus). Our study hopes to shed some new light on the cerebellar lateralization and investigate it from an extra (clinical) viewpoint of situs inversus. Situs inversus is a condition in which the major visceral organs are organized in a mirrored fashion. Following several studies by Vingerhoets (2018), there is reason to believe functional segregation, and lateralization specifically is differently organized in the situs inversus population. The variability in the situs inversus sample with respect to cerebral lateralization will be beneficial for the present study. In accordance with trends in the literature, we proposed that language and praxis would be lateralized to the right cerebellar hemisphere and spatial attention (and perhaps facial recognition) to the left cerebellar hemisphere. Our predictions were partially confirmed.

Word generation was found to be consistently lateralized to the right in the cerebellum.

Spatial attention showed a consistent cerebellar lateralization to the left. Both language and spatial attention carried over this consistency within the heterogenous situs inversus group. Cerebellar lateralization for praxis was consistently determined to the left within the control group, yet lost its consistency completely in the situs inversus group. Face recognition did not show a coherent cerebellar lateralization pattern. Our results fit well into the literature, yet establishing crossed cerebro-cerebellar relationships unfolded less evidently. A crossed cerebro-cerebellar relationship illustrated by a negative correlation between cerebellar and cerebral lateralization indices (LI), was only confirmed for language. However, it is reasonable to assume there is also a latent crossed cerebro- cerebellar relationship for spatial attention, though the small sample size and situs inversus heterogeneity made it difficult of it to be revealed.

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NEDERLANDSE SAMENVATTING

In de loop der jaren is steeds duidelijker geworden dat het cerebellum meer dan alleen motorische functies heeft. De betrokkenheid van het cerebellum bij niet-motorische processen werd ondersteund door anatomisch bewijs van cerebro-cerebellaire kanalen, evenals een breed scala aan klinisch en functioneel onderzoek. Cerebellaire lateralisatie tijdens cognitieve taken blijkt echter vaak omgekeerd te zijn in vergelijking met cerebrale functionele asymmetrie. We zullen cerebellaire lateralisatie onderzoeken in vier bekende gelateralizeerde taken (woordgeneratie, werktuig pantomime, ruimtelijke aandacht en gezichtsherkenning) in een steekproef van deelnemers met en zonder viscerale omkering (situs inversus). Onze studie hoopt een nieuw licht te werpen op de cerebellaire lateralisatie en deze te onderzoeken vanuit een extra (klinisch) oogpunt in relatie tot het situs inversus fenotype. Situs inversus is een aandoening waarbij de belangrijkste viscerale organen op een gespiegelde manier zijn georganiseerd. Na verschillende studies door Vingerhoets (2018) is er reden om te geloven dat functionele segregatie anders is georganiseerd in de situs inversuspopulatie. In overeenstemming met trends in de literatuur, stelden we voor dat taal en praxis naar de rechter cerebellaire hemisfeer en ruimtelijke aandacht (en misschien gezichtsherkenning) naar de linker cerebellaire hemisfeer lateraal georganiseerd zijn. Onze voorspellingen werden gedeeltelijk bevestigd. Woordgeneratie bleek consistent in het cerebellum naar rechts te zijn gelateralizeerd. Ruimtelijke aandacht vertoonde een consistente cerebellaire lateralisatie aan de linkerkant. Zowel taal als de ruimtelijke aandacht droeg deze consistentie over binnen de heterogene situs inversusgroep. Cerebellaire lateralisatie voor praxis werd consistent links bepaald binnen de controlegroep, maar verloor zijn consistentie volledig in de situs inversusgroep. Zoals verwacht vertoonde gezichtsherkenning geen coherent cerebellair lateralisatiepatroon. Onze resultaten passen goed in de literatuur, maar het leggen van gekruiste cerebro-cerebellaire relaties verliep minder vanzelfsprekend. Een gekruiste cerebro-cerebellaire relatie, geïllustreerd door een negatieve correlatie tussen cerebellaire en cerebrale lateralisatie-indices (LI), werd alleen bevestigd voor taal. Men kan echter aannemen dat er ook een latent gekruiste cerebro-cerebellaire relatie is voor ruimtelijke aandacht, aangezien de kleine steekproefomvang en situs inversus heterogeniteit het wellicht moeilijk maakte om deze te onthullen.

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1 INTRODUCTION

1.1 Cognitive functions of the cerebellum

Traditionally, the cerebellum is associated with motor demands. In the literature the cerebellum has classically been regarded to participate in the generation and control of movement. Most compelling evidence comes from clinical and anatomical, which link cerebellar damage to loss in motor control. Damage to these brain regions generates repercussions in motor function such as tremor and rigidity (Brooks & Thach, 1981). The innate cerebellar motor syndrome marks impairment of balance, limb dysmetria (lack of coordination of movement), dysarthria (lack of coordination of the motor-speech system) and oculomotor disorders (Holmes,1939). However, there is increasing evidence that the cerebellum has a broader functional role than just of the motor kind. This view is supported by the fact that the cerebellum body contains more than half of all the neurons in the brain (Rapoport, van Reekum, & Mayberg, 2000). Cognitive and other non-motor cerebellar functions (like emotion) have gained strong support over the years.

A major contributor to the controversy related to functional cerebellar organization is the cerebrocerebellar circuitry. Anatomical analysis can be a powerful tool to gain important insights into these other functional specializations of the cerebellum.

Particularly, identifying cerebellar input and output can help us associate cerebellar activation with cortical activations, hence, relating cerebellar activation to previously described cortical functions. Initially, this polysynaptic circuitry showed no conclusive evidence of nonmotor cerebellar function, because there were no cerebrocerebellar monosynaptic projections that could be picked up on using conventional anterograde and retrograde tracing techniques that do not cross the synapse. Conventional tract tracing techniques were thus unable to map the connection between the cortex and its projection zones in the cerebellum, because of the polysynaptic nature of the cerebrocerebellar projections. This apparent lack of cerebro-cerebellum connectivity contributed to the notion that the cerebellum was exclusively involved in motor functions. However, a couple of decades ago, a controversial observation arose and challenged this predominant assumption. In their landmark study, investigating functional anatomy of single-word processing, Petersen and colleagues (1988), observed a robust response in the right lateral cerebellum in their PET study. This was a particular region unconnected with the expected motor response in the anterior lobe of the cerebellum. Petersen et al. (1988) argued that this was a cognitive functional response rather than a sensorimotor one.

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Following this observation, multiple other studies examined cerebellar involvement in cognition by keeping the motor demands constant by means of e.g. automating the task (Raichle et al. 1994). The increasing development of human functional neuroimaging and more and more reports of cerebellar activation in cognitive tasks quickly generated a widespread assumption that these responses were non-motor. Stoodley et al. (2009) conducted a meta-analysis, in which it was clear that the literature is in a general agreement of cerebellar involvement in a number of cognitive tasks. However, the cerebro-cerebellar connection remained to be unravelled at that point. PET and fMRI approaches both assess brain activity indirectly through coupling neuronal activity and blood flow. These techniques can only provide indirect measures of cerebro-cerebellar connectivity. More direct evidence of cerebro-cerebellar connectivity beyond cortical motor regions was first shown by a transneuronal tracing study in monkeys, in which both input and output projections were investigated.

A cerebro-cerebellar connection was observed through two bidirectional pathways and implied broader cerebellar involvement in human cognition than was previously assumed. The two main pathways (cortico-ponto-cerebellar and cerebello-thalamo- cortical loops) link the cerebellum substantially with the motor cortices as assumed, but also with association cortices and paralimbic regions of the cerebral hemisphere (Kelly &

Strick, 2003; Middleton & Strick, 1994). Palesi and colleagues (2017) extended this notion of contralateral cerebro-cerebellar pathways to humans, by reconstructing the pathways in humans using in vivo tractography. This intricate connectional heterogeneity between different cerebellar regions and the cerebral cortex points to a large functional heterogeneity of different aspects of cognitive and emotional processing separately from motor functioning. Indeed, since the establishment of this circuitry, the cerebellum has been increasingly associated with a wide range of non-motor tasks, including executive functioning, learning, memory, attention, visuo-spatial regulation and language (see Baillieux, De Smet, Pquier, De Deyn, & Mariën (2008) for a full review).

A second important insight into non-motor functioning in the cerebellum is the dissociation between cerebellar motor syndrome (CMS) and the cerebellar cognitive affective syndrome (CCAS). Schmahmann and Sherman (1997) reported the clinically relevant parameters of the non-motor deficits in CCAS. This syndrome is predominantly characterized by executive, visual spatial, linguistic and affective deficits in patients with cerebellar damage. Additionally, language and other cognitive difficulties are shown to persist after cerebellar stroke, even after the cerebral motor syndrome has cleared up

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(Stoodley & Schmahmann, 2010). Following these findings, it was consistently reported that cerebellar damage in the posterior lobe led to the CCAS and not in the anterior lobe (Rapoport et al., 2000). Conversely, lesions in the anterior lobe lead more often to CMS, which was also in line with the functional topography of the human cerebellum conducted by Stoodley and Schmahmann (2008).

In conclusion, a non-motor role of the cerebellum has been established over the years. Cerebro-cerebellar bidirectional pathways support this notion, as well as the clinical condition of Cerebellar Cognitive Affective Syndrome. The anatomical research shows that cerebro-cerebellar are contralaterally connecting the cerebellum and cerebrum. This observation suggests that cerebellar functional segregation might be a mirror image of the cerebrum’s. We aim to investigate the functional lateralization of four cognitive cerebellar functions in our study. In what follows, an overview is presented of lateralization in general, lateralization approached from the view of a condition called situs inversus and implications for the cerebellar laterality.

1.2 Cerebral lateralization and Situs Inversus

1.2.1 Cerebral lateralization

Functional laterality in the brain implies cerebral hemispheric specialisation for specific cognitive functions and is believed to account for more efficient neural processing. Specifically, this improved efficiency through functional segregation is explained in terms of conflict prevention of separate functional regions, facilitation of parallel processing and enhanced neural capacity by eliminating redundant duplication (Vallortigara, Rogers, & Bisazza, 1999). Previous research has shown that stronger lateralization does not necessarily indicate better and more efficient processing.

Moreover, there appears to be an optimal interval that may be different for each cognitive function (Hirnstein et al., 2010). A prototypical lateralization and functional segregation in humans entails a left hemisphere dominance for language processing, praxis, and calculation and a right hemisphere dominance for spatial attention, prosody, and face recognition. We will investigate this functional asymmetry (in the cerebellum in particular) in relation to a condition called situs inversus.

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1.2.2 Cerebral laterality in Situs Inversus and implications for cerebellar lateralization research

Situs inversus is a condition in which the major visceral organs are organized in a mirrored fashion. More specifically, a typical organization of thoracic and abdominal organs would imply placement of the heart on the left side and the liver on the right side.

This normal visceral positioning is known as situs solitus (SS). Situs Inversus patients show either heterotaxy in the form of an entire reversal of thoracic and abdominal organs (situs inversus totalis) or a partial visceral reversal (situs ambiguus). This congenital condition is assumed to emerge in embryogenesis, due to complex genetic mechanisms of which the origins are not yet thoroughly understood (Vandenberg & Levin, 2010).

Approximately, 1 in 10,0000 adults are affected by situs inversus (Torgersen, 1950).

Research of anatomical brain asymmetries in situs inversus is scarce. The rather few studies consist of an autopsy report of one subject (Tubbs, 2003) and three neuroimaging studies (Kennedy et al., 1999; Ihara et al., 2003; Schuler et al., 2017).

In a recent paper, Vingerhoets, Gerrits and Bogaert (2018) studied functional lateralization of four cognitive functions in participants with situs inversus. Laterality in language function, face recognition, praxis and spatial attention was analysed. An important nuance to consider is the distinction between atypical organization (AFS) and reversed functional lateralization (rTFS) in general. In AFS the typical functional segregation is lost. However, in rTFS this typical functional segregation is maintained, but completely reversed, i.e. language and praxis are dominant in the right hemisphere, and face recognition and spatial attention in the left hemisphere. The functional organization of the brain was evaluated by Vingerhoets et al. (2018) through four cognitive localizer tasks. Language dominance was studied, with a verb generation experiment. Praxis was studied through a tool pantomime paradigm. Face perception was studied through a general procedure in which participants had to perceive faces and objects. Finally, spatial attention was investigated by means of a landmark task. The authors found that although participants generally showed typical brain organization, atypical functional segregation was observed significantly more frequently in situs inversus patients. Cognitive performance was also assessed and linked with the degree of atypical functional segregation. In praxis and spatial attention tasks this asymmetry significantly predicted participant’s performances, suggesting that typical functional segregation reflects better cognitive performance than deviations from the typical segregation standard. Vingerhoets et al. (2018) observed a general tendency consistent

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with the literature of left hemisphere dominant language and praxis and the right hemisphere for spatial attention and face perception, which can also be referred to as typical functional segregation (TFS). The functional lateralization in the situs inversus population varied to a higher degree than in the matched control group. The distinction between atypical organization (AFS) and reversed functional lateralization (rTFS) was demonstrated in their data. Foremost, atypical functional segregation was more commonly found in SIT (7 out of 15 cases) than in the matched control group (2 out of 15 cases). Remarkably, in some participants Vingerhoets et al. (2018) observed the standard functional lateralization of the cognitive tasks appeared to be completely reversed. Completely reversed typical functional segregation of the four different cognitive localizers was reported for 2 individuals: one SIT patient and one control.

Notably, the two participants with reversed functional segregation were both left-handed.

This would imply that this specific phenotype also manifests reversal of typical hand preference. However, this cannot be substantiated on account of Vingerhoets et al.

(2018) data because of their small sample size. This is not an exception in the literature, though. Two recent studies investigated atypical language dominance. Interestingly, atypical or right-hemispheric language dominance, occurred occasionally but appeared to be reported almost solely in left-handed participants (Mazoyer et al., 2014).

Vingerhoets et al. (2013) previously observed atypical lateralization for praxis in all individuals with atypical language dominance, whereas Cai et al. (2013) reported in their sample only left handed participants with atypical language dominance had atypical lateralization for spatial attention. Since these two studies both shared eight participants who were atypical language dominant and left handed, Cai et al. (2013) and Vingerhoets et al. (2013) were able to observe atypical lateralization of the three investigated functions in all eight left handed participants. However, none of the studies showed atypical language dominance without atypical functional segregation. Left handed individuals with atypical language dominance comprise approximately 20% of all left handed individuals (Knecht et al., 2000). To conclude, there is an assumption on account of their data, that left handed individuals are much more likely to indicate reversal of typical functional segregation than just solely atypical language dominance. This apparent left-handed phenotype is a relevant notion to take into account, when investigating cerebellar functional segregation.

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1.3 Crossed cerebellar lateralization

1.3.1 Evidence for crossed lateralization in the cerebellum

We investigate lateralization specifically at a cerebellar level. When Strick and colleagues initially employed the transneuronal tracing techniques using viruses in 1989, their results suggested that cerebellar connections to the association cortex lay between the mirrored motor connections. It was yet to be revealed if cerebral association connections located in this in-between area were crossed in the same fashion the motor representations are. Crucially for our objective, there is ample evidence that these cerebro-cerebellar pathways are in fact crossed, suggesting that the cerebellum’s functional segregation may be completely mirrored compared to the cortical segregation.

Resting state and spontaneous low-frequency fluctuations in brain activation have been proven to be useful in demonstrating this crossed relationship. Initially, Biswal et al.

(1995) established that fluctuations in primary motor cortex in resting-state were correlated with the contralateral motor cortex as well as the midline motor regions. Later on, Allen et al. (2005) also established that the in between area of crossed connections leads to crossed nonmotor functional lateralization in the cerebellum. Clinical, anatomical and functional evidence also supports these crossed cerebro-cerebellar fiber pathways in relation to cognitive tasks. In what follows, we present an overview of evidence suggestive of crossed cerebro-cerebellar lateralization for each of the four cognitive functions that are investigated in the present study.

1.3.2 Language

The language function in the cerebellum has been consistently demonstrated over time. Additionally, this relationship was predominantly reported to be a lateralized one. Previous anatomic investigations have demonstrated crossed reciprocal cerebro- cerebellar (BA 6, 44 and 45) connections in relation to language dominance, suggesting contralateral cerebellar activation even in right-hemispheric language dominant individuals (Leiner et al., 1986; Schmahmann, 1997). Generally, the left cerebral hemisphere is predominantly involved in language processing. However, as previously mentioned, about 10% show atypical right-hemispheric language dominance (Knecht et al., 2000). A strong relationship between handedness and language dominance has also been established that cannot be ignored. A systematic association has also been provided (Knecht et al., 2000 for a full review). Jansen et al. (2005) investigated whether

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the cerebellar contribution to the language function would be contralateral to the cerebral language dominance. They observed an exclusive crossed cerebro-cerebellar laterality in their data, regardless of handedness. Cerebellar activation associated with language was located in the lateral posterior cerebellar hemisphere (lobule VI, VII B, Crus I and Crus II). Clinical studies on patients with cerebellar disease likewise support a role for the right lateral cerebellum for language processing. Although lesions of both cerebellar hemispheres can influence linguistic abilities, right cerebellar lesions are more likely to do so (Fiez et al., 1992). The putative role of the cerebellum in language gained further support from voxel-morphometry (VBM) studies that observed differences in multiple cerebellar regions in dyslexics. Brown et al. (2001) reported reduced gray matter in right and left lobule VII of the (posterior) cerebellum of dyslexics. Similarly, Nicolson et al.

(1999) reported that, compared to a control population, the dyslexics exhibited significantly smaller right anterior lobes of the cerebellum. There is ample anatomo- clinical research on the cerebellar anatomy in dyslexics and taken together they suggest for selective regions of the cerebellum that are affected in developmental dyslexia.

However, it is important to mention that, like in these two examples, the regions in which these anatomical differences are found, are not consistent. On account of the similarities in the pattern of neuropsychological executive deficits in patients with cerebellar lesions and those with dorsolateral PFC lesions, Middleton and Strick (1994) proposed that the PFC areas of this loop are the same as the prefrontal regions recruited in verbal working memory. These neuropsychological symptoms included deficits in verbal fluency and other word generation abilities (Appollonio, Grafman, Schwartz, Massaquoi, & Hallett, 1993). However, Frank et al. (2007) investigated the conflicting results regarding cerebellar damage and the cerebellar involvement in language. They concluded there is an ongoing need for well-controlled lesion studies, which convincingly show that suggested language deficits are a direct consequence of cerebellar lesions independent of motor dysfunction and other confounding elements. Fiez et al. (1992) demonstrated in an important single-case study that patient’s performances with a right-sided infarction of the posterior-inferior cerebellar artery were deteriorated in a verb generation task. In contrast, Helmuth et al. (1997) found no such impairment in their population of nine adult patients with degenerative cerebellar lesions. In their examination of language functions following cerebellar damage, Frank et al. (2007) investigated verb generation in adults with degenerative and ischemic cerebellar lesions and concluded that there was no significant difference in performance between the patients and their matched controls.

Frank et al. (2007) proposed a number of factors that could account for this overall

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discrepancy. For example, a lot of studies, like those of Fiez et al. (1992) and Helmuth et al. (1997), only examined very few patients. Several methodological factors like presenting pictures as stimuli rather than written words (see Frank et al., 2007 for a full review). Their evidence suggests that cerebellar function in verb generation may be less pronounced than was previously assumed. In summary, while clinical studies generally point to a cerebellar involvement in language, the evidence is not unequivocal.

In comparison to the clinical data, functional neuroimaging research provides a more consistent trend. A whole range of language tasks seem to evoke cerebellar functional activation. In healthy populations, verbal fluency, verb-for-noun generation, semantic judgment and word stem completion tasks appear to reliably activate the cerebellum (Seger et al., 2000; Gurd et al., 2002; Hubrich-Ungureanu et al., 2002;

Noppeney & Price, 2002). Research also shows that greater cognitive demands in verbal fluency tasks seem to lead to more extensive cerebellar activation (Seger et al., 2000).

Stoodley and Stein (2010) conclude in their review of the cerebellar dyslexia hypothesis, that cerebellar activation during reading tasks in general involves motor but also non- motor cerebellar assets. Secondly, they determine that both lexical as well as sub-lexical and even semantic processing is shown to activate the cerebellum.

Given this evidence in relation to cerebellar language function, we will investigate this predominantly right lateralized cerebellar function in participants with and without SIT.

In their recent study Vingerhoets et al. (2018) reported brain structural and functional asymmetries in SIT patients related to language, but generally functional language lateralization in these patients appeared to be typically organized. On average the SIT patients showed reversed Yaklovian brain torque, but did not show atypical brain asymmetries (functional nor anatomical) associated with language. However, in their data-base, lateralization indices based on cortical activation are already established in all participants (whether they have AFS or r(TFS)) and will prove to be interesting to directly compare to our cerebellar indices.

1.3.3 Praxis

Secondly, we present support for cerebellar involvement in praxis through clinical studies of patients with apraxia. In line with Karl Hugo Liepmann’s postulations, we employ modern definitions of apraxia and characterize the disorder as a deficit in skilled motor actions that are not caused in any way by motor weaknesses, akinesia, movement disorders or general cognitive deterioration. Most forms of apraxia arise as a

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consequence of lesions in supratentrorial areas, including the inferior parietal lobe, the prefontal lobe of the left hemisphere and the corpus callosum (Mariën, van Dun, &

Verhoeven, 2015). However, recent anatomo-clinical evidence indicate that cerebro- cerebellar connections are involved in these pathophysiologies. More specifically, different forms of apraxia such as apraxia of speech, apraxic agraphia, constructional apraxia, drawing apraxia and mastication dyspraxia have been linked to cerebro- cerebellar functioning (for a review see Mariën et al., 2015). Vingerhoets and colleagues (2013) investigated cerebral lateralization of the praxis function in a representative population of right and left handed people. The authors concluded that handedness is not related to praxis lateralization, praxis was left lateralized in all cases. However, it can determine the strength of the lateralization. Now looking to cerebellar lateralization, we may expect right cerebellar lateralization for praxis due to crossed cerebro-cerebellar connections. Mariën and colleagues (2015) present some suggestive clinical evidence for this account. In a case study of a right-handed patient, for example, who suffered from a right cerebellar haemorrhage, Mariën et al. (2007) reported apraxic agraphia.

Praxis is generally strongly left lateralized in the cerebrum. The observation that praxis is left lateralized, neighbouring the left language functional mapping, endorses the widespread speculation that language might stem from the phylogenetically older praxis function. This ‘from grasp to language’ hypothesis thus posits that the language ability would have developed from the skill to use tools and perform learned movements (Arbib, 2008). The fact that Vingerhoets et al. (2018) found that not only the degree of language lateralization but also the praxis asymmetry was able to predict cognitive performance, supports this hypothesis. This could also add on to the assumption of right cerebellar (like in language) involvement but that remains speculation to date.

The anatomical work concerning the cerebro-cerebellar pathways of Palesi and colleagues (2017) through tractography, might also provide evidence for a spatial and praxis function of the cerebellum. A well-established connection between the cerebellum and the parietal lobe, led the authors to suggest a cerebellar involvement in response to the sight of an object, as well as grasping it, like is the case for the parietal lobe (Tunik, Frey & Grafton, 2005).

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1.3.4 Facial recognition

There is very limited support for a cerebellar involvement in face recognition.

However, we could tackle this issue through the cerebro-cerebellar pathways and look to projections of the temporal lobe. Rossion, Hanseeuw and Dricot (2012) aimed to identify the face-sensitive areas, by conducting a large whole-brain scale fMRI face localizer analysis. Six clusters were defined in relation to face processing: the fusiform face area (FFA), the pulvinar, the inferior occipital gyrus (OFA), posterior superior temporal sulcus, the amygdala and the anterior infero-temporal cortex. All of which were strongly right lateralized, both at group and individual levels. The fusiform gyrus largely comprises BA 37 and Palesi and colleagues (2017) reported in their tractography study that the temporal lobe projected strongly to the cerebellum, more so than any of the other lobes. This also included projections from BA 37, meaning that there could be a cerebellar involvement for face recognition on the grounds of this anatomical connection. A left cerebellar engagement could then be proposed on account of these contralateral connections.

1.3.5 Spatial attention

Because of the contralateral projections between the cerebral and cerebellar cortices it has been predicted that spatial attention is crossed as well. These large, though not exclusive, contralateral associations lead to the prediction that the right cerebellum is more engaged in spatial processing. These predictions have also been established in functional neuroimaging studies, showing that spatial tasks tend to be more left- lateralized in the cerebellum and are consistently involving posterior cerebellar lobe regions (Stoodley & Schmahmann, 2009a). Line bisection tasks, like the one of Vingerhoets et al. (2018), have shown the involvement of right parietal cortex but more importantly also the left cerebellum (Fink et al., 2000). Clinical reports support this left cerebellar lateralization as well. Visual spatial difficulties are more likely to arise after left cerebellar damage. For example, Gottwald, Wilde, Mihajlovic and Mehdorn (2004) demonstrated very clear impairments in visual attention tasks in their 21 patients with cerebellar lesions due to tumour or haematoma, in comparison with their matched controls. There results showed a greater language impairment observed in patients with a right-sided lesion.

Townsend and colleagues (1999) also previously reported greater attention- orienting deficits in patients with developmental cerebellar abnormality and in patients

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with cerebellar damage from stroke or tumor. However, these findings are not that consistent. Some researchers are not yet convinced about this cognitive visual spatial function and instead attribute cerebellar activations during these tasks to motor impairment or methodological problems. Ravizza and Ivry (2001), for example, demonstrated that lower motor demands reduced the deficits on an alternating attention task in cerebellar patients.

1.3.6 Summary

In conclusion, our study aims to further investigate the lateralization of nonmotor functions of the cerebellum. More specifically, we will investigate cerebellar lateralization for these four cerebrally lateralized cognitive functions. Contralateral cerebro-cerebellar pathways allow us to hypothesize that the cerebellum is lateralized in a mirrored fashion to the cerebral functional segregation. While a functional crossed cerebro-cerebellar lateralization is supported by anatomical, functional and clinical research for some functions, the evidence is less clear for other functions. Our study hopes to shed some new light on to cerebellar lateralization in given four cognitive functions. We will tackle this issue by studying a sample consisting of situs inversus patients as well as controls.

The variability in the situs inversus sample with respect to cerebral lateralization will be beneficial for the present study.

Using the dataset of Vingerhoets et al. (2018) gives us a unique opportunity to directly compare cerebral lateralization (which was then already established by the authors) with cerebellar lateralization on individual and group level. Based on the literature, we propose for language and praxis to be lateralized to the right cerebellar hemisphere and spatial attention (and perhaps facial recognition) to the left cerebellar hemisphere.

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2 METHODS & MATERIALS

2.1 Participants

The present study uses the same participant sample of Vingerhoets et al.

(2018). After the study was approved by the Research Ethics Committee, participants with situs inversus were identified by searching through the medical record databases of the Ghent University Hospital and Middelheim Hospital. Seventeen participants with SI and seventeen matched controls (based on sex, age, handedness and education) for each subject (SS) took part in this study and gave informed consent according to the Declaration of Helsinki. All participants (SI and matched controls) completed the same research protocol. The participants with SIT additionally gave written consent to provide access to the diagnostic radiological images that were consulted in order to assess the specific type of situs inversus, as well as possible comorbidities. Two participants were excluded from the study because one had situs ambiguus (a partial visceral reversal) and one was falsely labelled with situs inversus in the database. The final sample thus consisted of 15 individuals with situs inversus totalis (seven male, ages ranging from 18 to 50 years). Five participants have been diagnosed with Kartagener syndrome or primary ciliary dyskinesia: information which was obtained from their medical records. In the original stages of the study by Vingerhoets and colleagues (2018), handedness was not taken into account when controls were matched. Later on, given recent evidence of handedness being involved in neuroanatomy and cognitive performance (Marie et al., 2015), some matched controls were replaced. For our cerebellar lateralization investigation, we will also analyse these updated matched controls.

2.2 MR Acquisition

The MRI data of Vingerhoets and colleagues was collected using a 3.0 tesla TIM Trio (release VB17) MRI and standard 32-channel head coil (Siemens Healthineers, Erlange, Germany). A high-resolution anatomical scan of the whole brain was first carried out using an MPRAGE sequence with a resolution of 1.0x1.0x1.0 mm³ and 176 sagittal slice (TR/TE/TI=2250/4.18/900 ms, flip angle = 9°). The functional scans were T2*

weighted echo planar images (EPI) with blood oxygenation level-dependent (BOLD) contrasts. These were all acquired with voxel size 3.0x3.0x2.5mm³, FOV = 192mm, 33 ascending axial slices, TR/TE=2500/27ms, flip angle=62° and PAT=2. The stimuli were

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back projected on a display at the back of the magnet bore and viewed through a mirror attached to the head coil.

2.3 Functional brain imaging

Vingerhoets et al. (2018) selected four functional localizer paradigms reported to produce lateralized activation in previous neuroimaging research (Cai, Van der Haegen,

& Brysbaert, 2013; Cicek, Deouell, & Knight, 2009; Fox, Iaria, & Barton, 2009;

Vingerhoets et al., 2012). Two tasks, word generation and tool pantomiming, generally elicit left lateralized activation, and two other tasks, the landmark task (assessing spatial attention) and face recognition, are known to predominantly produce neural responses in the right hemisphere. Paradigms were assessed in a fixed order starting with the pantomime task, then face recognition, landmark task, and word generation.

2.3.1 Tool Pantomime Paradigm

Stimuli

The implemented task was a shorter version of the paradigm used to study praxis lateralization (Vingerhoets et al., 2012; Vingerhoets et al. 2013). During every trial, two objects are presented to the participant in color, one on the right and one on the left side of the display. There are 20 pairs of stimuli. In the tool conditions the pair of objects are familiar tools that are often used together, like a needle and a thread or a pencil and a sharpener. In each pair, one object is meant to be used actively (like a pencil) and another passively (sharpener). In half of the trials in the tool condition, the ‘active tool’ would be displayed on the left side of the screen and the other half of the trials they would be on the right. In the control condition, the objects were eggs. This was implemented to control for object-related movements in general. Eggs are familiar objects to the participants, but are obviously not related with tool-like gestures. During these trials, one of the eggs was displayed vertically (turned 90° degrees). The egg that was aligned vertically was on the left in half of the trials and on the right side in the other half.

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Task

Participants were asked to pantomime holding and using the tools, along with the positions they were displayed in. More specifically, when a presented utensil, e.g. a sharpener, was presented on the left and a pencil on the right, participants would pantomime the act of sharpening the pencil, with the sharpener in the left hand and the pencil in their right one. These bimanual acts entail that one hand has to perform a positioning task and the other hand a manipulation task. Hence, left and right handed participants were expected to perform these tasks differently. By switching the position of the utensils in half of the trials, Vingerhoets et al. (2018) could make an abstraction of the hand performing the (dominant) movement, i.e. participants had to pantomime the manipulative (dominant) movement an equal amount of times with their dominant as with their non-dominant hand. During the control conditions, participants were instructed to pantomime holding one egg in a central position, while they rotated the other egg around it. The “vertical” egg symbolized the side (hand) with which the dominant (rotating) movement had to be made and it appeared on either side in equal occasions. These instructions make up four different conditions: (1) bimanual right dominant tool pantomime, (2) bimanual left dominant tool pantomime, (3) bimanual right dominant control pantomime, and (4) bimanual left control pantomime. The functional neuroimaging contrast of interest opposed the control conditions against the pantomimes tools conditions. The four conditions were arranged in four subsequent blocks. Their paradigm was organized in the form of a conventional block design with four conditions. Each condition contained eight blocks. A block lasted 21 s and contained 6 stimuli of the same type each presented for 3500 ms. The total paradigm thus took 11.2 min to complete.

Blocks were presented in a semi-random order to avoid the subsequent presentation of two blocks with the same type of stimuli. Stimuli were randomly distributed over their conditions’ blocks. The performance of the participants was monitored by observing the pantomimes of the volunteer inside the magnet. All participants were able to perform the required pantomimes during their fMRI session. To avoid movement artefacts, Vingerhoets et al. (2018) asked the volunteers to perform the pantomimes in a calm fashion and they were only allowed to use their underarms, wrists, and hands. The contrast of interest for tool pantomime was tool pantomimes > control pantomimes.

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2.3.2 Face Recognition Paradigm

Stimuli

Videoclips of faces and non-living objects were presented to the participants in separate blocks (Fox et al. 2009). The face videoclips showed dynamic emotional changes from neutral to happy. The videos of objects depicted different types of motion that avoided big translations in position. This was made sure to make the dynamic changes of the objects more or less comparable to the dynamic changes seen in faces.

The video-clips were resized to a width of 400 pixels and lasted 2000 ms each.

Task

Participants had to perform a one-back task, during which they were asked to press a button if an image was identical to the previous one. Identical fixation blocks were alternated with image blocks that lasted 12 s and consisted of six video-clips (five novel and one repeated). Each image category block was presented 8 times in a counterbalanced order, so that the entire paradigm lasted 6.6 minutes. The contrast of interest opposed the dynamic face perception condition against the dynamic object condition.

2.3.3 Landmark task Paradigm

Stimuli

Vingerhoets et al. (2018) used black lines comprising a 15 cm horizontal line spanning a visual angle of 8° and a short vertical line that were displayed on a white background. The stimuli were each presented for 1.6 s.

Task

The task Vingerhoets et al. (2018) used, contained six experimental blocks (LM- condition), six control blocks (LMC-condition), and six rest periods (fixation cross) following procedures established by Cicek and colleagues (2009). LM and LMC-blocks were preceded by a 4 s instruction display that indicated the task to be performed. Each block contained 12 trials in a random order and took 21.6 s to complete. Within the LM- blocks, the vertical mark could be centered on the horizontal line, either exactly in the middle of the line (50% of the trials), or slightly deviated to the left or to the right side (the other 50% of the trials). Deviations could be either 2.5, 5.0, or 7.5% of the length of the

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horizontal line. Participants then had to decide whether the line was bisected precisely in the middle or not, and to indicate an exact bisection by pressing a button with the left index finger, and to press another button with the left middle finger if they thought this was not the case. In the LMC-blocks, the stimuli were identical to the LM condition except that in half of the trials, the small vertical mark was placed directly through the horizontal line and in the other half of the trials it was displayed a little above the horizontal line and did not touch the line. Participants were required to judge whether the vertical mark touched the horizontal line (left index finger press) or not (left middle finger press). There was an interval of 200 ms between trials. A fixation task took place between each LM- and LMC-block. The total paradigm took 7.6 min and the contrast of interest compared LM > LMC conditions.

2.3.4 Word generation Paradigm

Stimuli

Vingerhoets et al. (2018) adapted a Dutch version of a word generation paradigm to assess language dominance (Cai, Paulignan, Brysbaert, Ibarrola, & Nazir, 2010). The stimuli consisted of ten letters (b, d, k, l, m, n, p, r, s and t). Letter selection was based on a pretest with native Flemish-Dutch speakers. This allowed for exclusion of letters with which participants in previous studies only could generate a few words. Stimuli were displayed in white on a black background.

Task

The task contained 10 cycles. Each cycle had one word generation block (15s), one control block (15s), and two 15s rest periods between the tasks. A cycle began with a word generation block during which a letter was shown in the middle of the display and participants were asked to covertly generate as many words as possible that started with that letter. Then a rest period followed, during which a short line was shown on the screen and participants were asked to relax. In the following control block, the letter sequence

“BABA” was shown on the screen and participants were instructed to covertly repeat baba, which is pronounceable but has no meaning in Flemish-Dutch. After the control block, there was another rest period. This four-block cycle was repeated 10 times with different letters in random order. The task took 10 min to complete and the investigated contrast was letter fluency > baba.

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2.4 fMRI data processing

Brain Voyager QX was used to analyse and preprocess the fMRI data.

Preprocessing consisted of slice scan time correction, followed by 3D motion correction and temporal filtering. The functional data was then normalized to MNI space and spatially smoothed using a Gaussian filter. The BOLD activation in every condition was then modeled by convolving the defined conditions with a standard canonical hemodynamic response function in order to form the main independent predictors to use in the General Linear Model (GLM). Finally, an independent component analysis (ICA) was performed to determine the noise predictors which were subsequently included in the GLM of the fMRI data as predictors of no interest. Potential task-related ICA components (r>|.30|) were taken out and only the remaining ICA components were included in the GLMs.

2.5 Explorative group averages in functional brain data

In order to identify a functional brain activation tendency within the situs inversus and situs solitus group, we conducted a multi-subject general linear model analysis. In every situs group, we conducted a random effects general linear model analysis for each task (word generation, face recognition task, praxis task and landmark task). This analysis was performed to obtain a (visual) group average of the fMRI activation in each task.

2.6 Individual cerebral & cerebellar lateralization

2.6.1 Cerebral lateralization

For every cognitive localizer task, regions of interest (ROI) were determined, coinciding with brain areas that were previously put forward in clinical studies when damage occurred. Lesions in Brodmann areas 44 and 45 for disrupted letter fluency (Baldo, Schwartz, Wilkins, & Dronkers, 2006; Costafreda et al., 2006; Price, 2012).

Brodmann areas 6, 39, 40, and 44 were outlined for tool pantomime (Buxbaum, Kyle, Grossman, & Coslett, 2007; Goldenberg, Hermsdorfer, Glindemann, Rorden, & Karnath, 2007). For spatial attention, Brodmann areas 19, 22, 37, 39, 40, and 44 were considered on the basis of clinical work done by Hillis and colleaugues (2005). Finally, Brodmann area 37 was outlined for face perception (Barton, 2008). These Brodmann areas were

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defined within each participant based on the segmented image of each individual’s structural brain scan. Cerebral (consisting of left and right) hemisphere surfaces were constructed along the gray–white matter border, and were visually checked and manually corrected when necessary. The individual cortical surface reconstructions were matched to Brodmann area templates, to yield subject-specific ROIs.

2.6.2 Cerebellar lateralization

Subject-specific cerebellar ROIs were constructed by manually delineating the whole left and whole right cerebellar hemispheres on the participant’s T1 anatomical image. We opt to look for entire cerebellar hemispheres because of the limited resolution and the fact that the original research intent of Vingerhoets et al. (2018) described the cortex and aimed to get an optimal cerebral view.

2.6.3 Determination of individual laterality indices (LI)

Lateralization for each localiser was assessed by calculating subject-specific laterality indices (LIs).The procedure to establish the cerebral laterality indices was identical to that of the cerebellar LIs. Using the individual cerebral hemispheres (or cerebellar masks), region-of-interest analyses were conducted for each localizer task.

Specific contrasts were implemented for each task. For praxis, the investigated contrast was control pantomimes > pantomimes of tool. To investigate the Landmark task, the contrast of interest studied the landmark conditions > landmark control conditions. For face perception, the contrast of interest compared dynamic face perception > dynamic object perception. Finally, in word generation data the contrast of interest was letter fluency > baba.

To calculate a lateralization index (LI), the amount of the significant voxels on each side were calculated. This procedure was based on the magnitude of signal change, like in Fernandez and colleagues’ (2001) work, by selecting voxels above a particular threshold (mean t-value of 5% most active voxels divided by 2) over the left and right cerebral (or cerebellar) hemisphere taken together. Finally, a lateralization index was calculated on the summation of the t-values between the left and right cerebral (or cerebellar) sites. The final LI value is calculated by subtracting right t-values with left t values, which is then divided by the summation of left and right t values. An LI that is negative indicates a bigger amount of active voxels in the left hemisphere (left lateralization), whereas a positive LI indicates the opposite (right lateralization). The cerebellar LIs were compared with LIs of the cerebrum, previously established by Vingerhoets and colleagues (2018).

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3 RESULTS

3.1 Cerebro-cerebellar lateralization

First, we investigated cerebral and cerebellar lateralization for the whole participant group. Face recognition in the cerebrum was on average lateralized to the right (indicated by the positive value; M LI = 0.38, SD = 0.57). However, the task was (slightly) lateralized to the left the cerebellum (M LI = - 0.07, SD = 0.45). Spatial Attention was on average lateralized to the right in the cerebrum (M LI = 0.51, SD = 0.47) and to the left in the cerebellum (M LI = - 0.48, SD = 0.57). Mean LIs for praxis pointed to left cerebral lateralization (M LI = - 0.32, SD = 0.49) and right cerebellar lateralization (M LI

= 0.14 SD = 0.57). Finally, in the word generation task we observed left lateralization in the cerebrum (M LI = - 0.56, SD = 0.50) and right cerebellar lateralization (M LI = 0,46, SD = 0.46).

Next, we investigated the relationship between cerebral and cerebellar lateralization directly by calculating Pearson’s correlations between cerebellar and cerebral LIs for the four localizer tasks. Table 1 shows an important overview of Pearson’s

ρ correlations between cerebellar and cerebral LIs of the different tasks. This table will be referred to frequently along this results section. Considering the complete data set, only for the word generation task a significant negative correlation between cerebral and cerebellar LIs was found (ρ = - 0.71, p = 0.013). The landmark task, produced a negative correlation as well, however it failed to reach significance (ρ = - 0.34, p = 0.066). Face recognition and praxis tasks did not yield significant correlations between cerebellar and cerebral LIs (ρ= 0.07, p = 0.748 & ρ = - 0.30, p = 0.104; respectively).

Table 1. An overview of all Pearson’s R correlations grouped by task.

Face Recognition Landmark Praxis Word Generation

ρ(SI) 0,26 -0,35 0,51* -0,78***

p(ρ) 0,359 0,203 0,0455 0,000

ρ(SS) -0,01 -0,36 0,07 -0,47

p(ρ) 0,733 0,188 0,791 0,070

ρ(Total) 0,07 -0,34 0,30 -0,71*

p(ρ) 0,748 0,066 0,104 0,013

Note. Each row represents a different sample set: situs inversus group, situs solitus group, and the complete sample. Significant correlations are indicated in bold. P values are stated below each correlation. One star accompanying Pearson’s R is p<0.05, two stars is p<0.01 and three stars is p<0.001.

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26/41 Figure 1. Scatterplots illustrating possible relationships between the two sets of LIs

(cerebellar and cerebral), grouped by localizer task. Statistical analyses showed only a significant negative correlation within the word generation task, when taken into account the whole data set (ρ = -0.71, p = 0.013), which is why its accompanying trendline was indicated in red. Spatial attention produced a bordering significant negative correlation (ρ

= - 0.34, p = 0.066), and is therefore presented in blue. Non-significant correlations are illustrated with a dotted (black) trendline.

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3.2 Group comparison

3.2.1 Situs Solitus

We then consider the situs solitus group (i.e., the matched control group), to identify a general tendency of cerebro-cerebellar lateralisation patterns. Based on cortical lateralization patterns, twelve individuals could be considered as having a Typical Functional Segregation (TFS). Two cases (SS05 and SS11) were identified as an Atypical Functional Segregation (AFS) and one participant (SS16) as a Reversed Typical Functional Segregation (rTFS).

On average within the situs solitus group, brain activation in the cerebrum for Face Recognition was lateralized to the right (M = 0.482, SD = 0.553), as well as Spatial Attention (M = 0.657, SD = 0.340). Praxis (M = -0.364, SD = 0.446) and Word Generation (M = - 0.679, SD = 0.424) were left lateralized in the cerebrum. The opposite pattern was observed in the cerebellum LI averages. Face recognition lateralization in the cerebellum yielded an average LI value of -0.131, illustrating left cerebellar lateralization. Spatial attention showed left cerebellar lateralization (M = 0.6576). Praxis was on average right lateralized in the cerebellum with an average LI of 0.2753. Finally, word generation showed an opposite (right-sided) average in the cerebellum as well (M = 0.6445).

Resulting lateralization indices for each cognitive localizer and each control participant are listed in Table 2. The overview pictures cerebellar LIs adjacent to cerebral LIs, grouped by cognitive localizer. Mean LIs are also given below each task-pairing.

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28/41 Table 2. Resulting LIs for each cognitive localizer within the matched control group (Situs Solitus).

Note. LIs were color coded using red for left hemisphere dominance and green for right hemisphere dominance. Every first column within a localizer task division represents the cerebellar LI and every second one the cerebral LI.

Secondly, we look at the possible relationship between cerebellar and cerebral lateralization. Considering correlations within the control group, there was no significant Pearsons correlations obtained between cerebellar LIs and cerebral LIs (see Table 1).

No localizer task showed a clear relationship. Only word generation LIs were almost significantly (and negatively) correlated (ρ = -0.47, p = 0.070). Figure 2 depicts the scatterplots illustrating possible relationships between the two sets of LIs (cerebellar and cerebral) within the control group.

Face Face (cerebrum)

Landmark Landmark (cerebrum)

Praxis Praxis (cerebrum)

W Gen W Gen (cerebrum)

SS02 0.156 0.492 -0.592 1 -0.637 -0.764 0.678 -0.992

SS03 0.757 0.593 -0.903 0.886 0.414 -0.154 0.770 -0.219

SS04 -0.552 0.002 -0.598 0.863 0.099 -0.259 0.801 -0.990

SS05 -0.857 0.980 -0.922 0.684 0.901 0.157 0.994 -0.484

SS06 -0.595 0.686 0.809 0.294 0.866 -0.223 0.264 -0.845

SS07 -0.594 0.940 -0.996 0.893 0.831 -0.514 0.917 -0.790

SS08 0.501 1 -0.970 0.956 -0.400 -0.560 0.677 -0.841

SS09 0.368 0.743 -0.960 0.781 0.425 -0.789 0.463 -0.512

SS11 -0.081 -0.818 -0.932 0.145 0.693 -0.271 0.270 -0.803

SS12 0.178 0.685 -0.570 0.767 -0.556 -0.692 0.992 -0.994

SS13 -0.420 0.934 -0.225 0.262 0.363 -0.583 0.690 -0.985

SS14 0.022 0.432 -0.919 0.834 0.366 -0.148 0.409 -0.784

SS15 -0.402 0.299 -0.478 0.869 0.699 -0.738 0.650 -0.580

SS16 0.073 -0.570 -0.204 -0.116 -0.262 0.865 0.094 0.611

SS17 -0.520 0.839 0.8044 0.747 0.325 -0.789 0.995 -0.972

M(SS) -0.131 0.482 -0.510 0.658 0.275 -0.364 0.645 -0.679

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Figure 2. Scatterplots illustrating possible relationships within the control group (SS) between the

two sets of LIs (cerebellar and cerebral), grouped by localizer task. The control group data failed to produce significant correlations between cerebellar and cerebral LIs. However, the word generation data yielded a borderline significant negative correlation between cerebellar and cerebral LIs, and its trendline is therefore presented in blue (ρ = -0.47, p = 0.070). Non-significant correlations are illustrated with a dotted (black) trendline.

Cerebral and cerebellar intensity in word generation was also most comparable in strength, with a mean LI of 0.6445 and -0.679, for cerebellar and cerebral LIs respectively. The cerebral lateralization in the one case of Reversed typical functional segregation (SS16) was not mirrored in the cerebellar lateralization. Neither was the cerebral lateralization within the two cases of atypical functional segregation (SS05 &

SS11) mirrored in the cerebellar laterality indices.

IF THE CEREBRUM GETS ALL OF IT RIGHT, IS THERE SOMETHING LEFT FOR THE CEREBELLUM?