Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing

2.2 Spinal and olivary inputs to cerebellum differentiate motor versus nonmotor regions

The cerebellum receives extensive projections carrying cutaneo-kinesthetic information from the limbs directly via the spinocerebellar tracts and from the face and head via the trigeminocerebellar tracts, and indirectly via the nuclei of the inferior olivary complex relaying afferents conveyed in the spino-olivary tracts. In cat the dorsal and ventral spinocerebellar tracts terminate in the anterior lobe and lobule VIII (Brodal, 1981); the trigeminocerebellar projections terminate in the face representation principally in lobule VI, with some extension into lobules V and sparse involvement of lobules VII and VIII (Carpenter and Hanna, 1961; Hesslow, 1994; Ikeda, 1979; Snider, 1950). The medial and dorsal accessory olivary nuclei relay their spinal inputs through climbing fibers to these same cerebellar lobules (lobules I-V; VI; VIII) as well as to the interpositus nuclei (Brodal, 1981; Oscarssson, 1965; Voogd, 2004).

In contrast, the principal olivary nucleus, which has little or no spinal cord input (Sugihara and Shinoda, 2004), sends climbing fibers to lobule VII and the dentate nucleus, and to a smaller degree to lobule VI, but not to the anterior lobe or lobule VIII. This double dissociation in the olivo-cerebellar connections is evident in now-classical anatomical studies (Brodal, 1981; Oscarsson, 1965) as well as in contemporary anatomical investigations (see Azizi, 2007 for review), and provides part of the anatomical substrate for our proposed cerebellar motor-nonmotor dichotomy.

2.3 Motor, cognitive, and limbic loops in the cerebrocerebellar system

The cerebellum is linked to the cerebral cortex via two-stage feedforward and feedback systems. Input from cerebral cortical regions terminates on nuclei in the basis pontis, which in turn convey mossy fiber efferents to the cerebellum. Feedback projections from the cerebellar cortex travel via the deep cerebellar nuclei and terminate in the thalamus, which then sends projections back to the cerebral cortex. The organization of the cerebro-cerebellar system indicates that information from sensorimotor vs. association cortices is processed in different regions of the cerebellum.

3.1 Sensorimotor cerebellar activation

The somatotopic representations of the human body have been demonstrated using functional MRI during sensorimotor tasks (Bushara et al., 2001; Grodd et al., 2001, 2005; Nitschke et al., 1996; see also Takanashi et al., 2003; Thickbroom et al., 2003). These are reflected in a body map in the anterior lobe and lobule VI with a second representation in lobule VIII of the posterior lobe, corresponding well with electrophysiological studies in the cat (Snider and Eldred, 1951). Movement of the hand localizes to ipsilateral lobules V and VIII (Grodd et al., 2001); tactile stimulation of the hand activates lobule V ipsilaterally with a second area of activation in lobules VIIIB and IX (Bushara et al., 2001). Leg and foot sensorimotor representations are observed in lobules II and III (Nitschke et al., 1996), whereas orofacial movements activate paravermal anterior lobe regions extending into medial parts of lobule VI (Dresel et al., 2005; Urban et al., 2003). Our meta-analysis corroborated selected aspects of the somatotopy identified in these and other studies; activation patterns for sensorimotor tasks involving the right index finger were localized to the anterior lobe (lobule V), with a secondary focus in lobules VIIIA/B (Stoodley and Schmahmann, 2009a).

3.2 Cerebellar activation during cognitive tasks

Activation of the cerebellum in cognitive tasks was first demonstrated in positron emission tomography (PET) studies of language (Petersen et al., 1998; Raichle et al., 1994). Subsequent evaluations showed cerebellar activation in a variety of nonmotor tasks including sensory processing (Gao et al., 1996), appreciation of timed intervals (Jueptner et al., 1995), anticipatory planning and prediction (shifting attention tasks) (Allen et al., 1997; though see Bischoff-Grethe et al., 2002), verbal working memory (Desmond et al., 1997), and mental imagery (Ryding et al., 1993). Since these early studies, cerebellar activation has been found consistently during language, working memory, visual spatial and executive function tasks.

Verbal fluency, verb-for-noun generation, semantic judgment, and word stem completion tasks reliably activate the cerebellum in healthy populations (Buckner et al., 1995; Desmond et al., 1998; Frings et al., 2006; Gurd et al., 2002, Herholz et al., 1996; Hubrich-Ungureanu et al., 2002; Lurito et al., 2000; McDermott et al., 2003; Noppeney and Price, 2002; Ojemann et al., 1998; Raichle et al., 1994; Schlosser et al., 1998; Seger et al., 2000; Tieleman et al., 2005; Xiang et al., 2003). These studies controlled for articulation or employed paradigms that did not require subjects to verbalize their responses, and found activation in the posterior lobe, including lobules VI and VII (Crus I/II). In particular, language-related tasks activate the right posterolateral cerebellum in right-handed individuals, in concert with left prefrontal regions (Buckner et al., 1995; Desmond et al., 1998; Fiez and Raichle, 1997; Gurd et al., 2002; Ojemann et al., 1998; Palmer et al., 2001; Petersen et al., 1998; Schlosser et al., 1998). Laterality of cerebellar activation varies according to cerebral hemisphere dominance for language – right cerebellar activation occurs during verbal fluency (word generation) and working memory tasks in right-handed subjects (Hubrich-Ungureanu et al., 2002; Jansen et al., 2005; Ziemus et al., 2007), whereas the left cerebellum activates during these tasks in left-handed subjects (Jansen et al., 2005). Our meta-analysis (Stoodley and Schmahmann, 2009a) provided further evidence that language-related activity is focused in lateral, posterior cerebellar regions, including lobules VI and Crus I/II. Notably, the cerebellar anterior lobe is not active when the motor components of speech (articulation) are excluded, although it has been argued that cerebellar activation during cognitive tasks reflects inner speech or subvocal rehearsal (e.g., see Ackermann et al., 2007).

Also reflecting these contralateral cerebro-cerebellar connections, cerebellar activation patterns during spatial tasks tend to be more left-lateralized, consistently involving posterior lobe regions, particularly lobule VI (Stoodley and Schmahmann, 2009a). This is exemplified by line bisection tasks that involve the right parietal cortex and left cerebellum (Fink et al., 2000). Mental rotation and spatial transformation tasks also tend to activate posterior regions in lobules VI / Crus I (e.g., Bonda et al., 1995; Jordan et al., 2001; Parsons et al., 1995; Vingerhoets et al., 2002; Zacks et al., 2002).

Working memory paradigms, such as the n-back task, activate bilateral regions of the cerebellar posterior lobe (Honey et al., 2000; LaBar et al., 1999; Tomasi et al., 2005; Valera et al., 2005). Chen and Desmond (2005a,b) have proposed that the superior cerebellum (lobules VI/Crus I) is involved in the articulatory control aspect of this task while the inferior cerebellum (lobules VIIB/VIIIA) is important for phonological storage. Cerebellar posterior lobe activation is also found during executive function tasks, such as the Tower of London, random number generation and complex decision-making tasks (Blackwood et al., 2004; Daniels et al., 2003; Harrington et al., 2004; Jahanshahi et al., 2000; Schall et al., 2003), and tends to specifically involve regions within lobules VI/Crus I and VIIB on the left (Stoodley and Schmahmann, 2009a).

A consistent feature of the cerebellar activation by tasks of cognitive processing such as language, working memory, spatial and executive tasks is that it is located in the posterior lobe and does not involve the anterior lobe.

3.3 Cerebellar regions active during affective processing

Functional imaging of affective / emotional processing in healthy controls also highlights posterior cerebellar regions. Viewing emotional vs. neutral images from the International Affective Picture Scale (IAPS; Lang et al., 2005) activates cerebellar regions in the posterior lobe, including lobules VI and VII (Bermpohl et al., 2006; George et al., 1993; Hofer et al., 2007; Lane et al., 1997; Lee et al., 2004; Paradiso et al., 1997, 1999, 2003; Takahashi et al., 2004). The act of identifying emotional intonation produces cerebellar activation in midline lobule VII and the lateral posterior hemisphere (lobule VI bilaterally and right Crus I) both during fMRI (Wildgruber et al., 2005) and PET imaging (Imaizumi et al., 1997).

Cerebellar vermis activation is seen in neuroimaging studies investigating panic (e.g., Reiman et al., 1989), sadness and grief (Beauregard et al., 1998; Gundel et al., 2003; Lane et al., 1997). Autonomic processing (Parsons et al., 2000), including the autonomic cardiovascular arousal that occurs during both exercise and mental arithmetic stressor tasks (Critchley et al., 2000), and air hunger (Evans et al., 2002) result in activation of posterior cerebellar regions in both the midline and lateral hemispheres. The cerebellum is also active during painful stimulation (Becerra et al., 1999; Borsook et al., 2007; Ploghaus et al., 1999; Singer et al., 2004) – anterior regions are activated by the experience of pain, whereas posterior regions are active during the anticipation of pain (Ploghaus et al., 1999). Further, different cerebellar regions are involved when processing one’s own painful experience (posterior vermis) as opposed to experiencing empathy for another’s pain (lobule VI; Singer et al., 2004). The activation of hemispheral lobule VI and vermal lobule VII is quite consistent across these studies of emotionally salient stimuli (Stoodley and Schmahmann, 2009a), and like the activation patterns seen within the cerebellum for cognitive tasks, the focus of the cerebellar activation varies according to the demands of the task. It is possible that hemispheric lobule VI and VII activation reflects more cognitive components of task performance (e.g., empathy), due to the connections of these regions with association cortices, and more “limbic” tasks (including autonomic processing) may particularly involve the posterior vermis, our putative limbic cerebellum.

4.2 Cognitive and affective symptoms from posterior lobe damage

If damage to lobules VI and VII largely spare motor function, what are their functional roles? Clinical findings provide support for regional functional specialization in cerebellum of cognitive and affective processes, and they point to the posterior lobe, not the anterior lobe, as being critical in this regard (e.g., Exner et al., 2004; Schmahmann et al., 2009b; Schmahmann and Sherman, 1998; Tavano et al., 2007).

This work was supported in part by R01 MH067980, the Birmingham Foundation, and a Fund for Medical Discovery Award to CJS from the Executive Committee on Research of Massachusetts General Hospital.