Neurology classically considers the cerebellum in relation to ataxia
, i.e., the motor consequences of cerebellar damage. Ataxia (from the Greekα–ταξισ, meaning “lack of order”) is a neuropathological state consisting of gross lack of coordination of muscle movements. It is caused by dysfunction of those parts of the nervous system that coordinate movement and it includes forms of cerebellar, sensory, and vestibular origin. Cerebellar ataxia is expressed through a variety of elementary neurological deficits, such as antagonist hypotonia, asynergy, dysmetria, dyschronometria, and dysdiadochokinesia. How and where these abnormalities manifest themselves depends on which cerebellar structures have been damaged and whether the lesion is bilateral or unilateral. In very general terms, we can observe three main groups of symptoms4
- impairment of body balance (Romberg test) and of eye movement control (saccade alterations, nystagmus) due to specific dysfunction of the vestibulocerebellum;
- impairment of gait (wide-based, “drunken sailor” gait, characterized by uncertain starting and stopping, lateral deviations, and uneven steps) due to dysfunction of the spinocerebellum;
- difficulty executing voluntary, planned movements due to impairment of the cerebro-cerebellum. Disturbances include intention tremor (coarse trembling, accentuated on the execution of voluntary movements, possibly involving the head and eyes as well as the limbs and torso), peculiar writing abnormalities (large, uneven letters, irregular underlining), and a peculiar pattern of dysarthria (slurred speech, sometimes characterized by explosive variations in voice intensity despite a regular rhythm).
Quite apart from their undisputed clinical importance, these observations lend support to the idea that different motor functions are localized in specific cerebro-cerebellar loops and that the lateral cerebellum is involved, through cerebro-cerebellar loops, in the cognitive components of movement planning. In addition, on careful analysis, patients with focal cerebellar lesions have also been found to show cognitive-affective alterations (Schmahmann and Sherman, 1998
) constituting a picture that might be called dysmetria of thought
. The concept of “dysmetria of thought” or “cognitive dysmetria” has been proposed as a unitary neurocognitive framework of reference for schizophrenia symptoms [(Andreasen et al., 1998
), see below] and involves a neural network with the main nodes in the prefrontal cortex (PFC), thalamus, and cerebellum. Cognitive dysmetria comprises:
- impairment of executive functions, such as planning, set-shifting, abstract reasoning, working memory, and verbal fluency;
- difficulties with spatial cognition, both in visuospatial organization and visuospatial working memory;
- personality change, with blunting of affect and/or disinhibited and inappropriate behavior;
- language deficits including agrammatism, dysprosodia, and mild anomia.
This constellation of symptoms, which is reminiscent of a prefrontal syndrome (Schmahmann, 2004
; Schweizer et al., 2007
), is called cerebellar cognitive affective syndrome
. Clearly these symptoms are not exclusive to cerebellar damage; indeed, the aforementioned cognitive and affective alterations can also be found in patients with disorders of the cortical associative areas (especially prefrontal) and paralimbic areas, or with disorders of the subcortical areas to which the former are connected. It would be safe to say that these symptoms involve the whole CTCC loop. Anatomically, lesions of the posterior lobe are associated, in particular, with cognitive symptoms, while lesions of the vermis are consistently observed in patients with pronounced affective alterations. The anterior lobe seems to be less involved in the generation of these cognitive and behavioral deficits, while anterior lobe lesions are well-known to cause motor ataxia (Diener and Dichgans, 1992
) (Figure ). Functional neuroimaging studies have consistently shown: (1) activation in the anterior lobe during motor learning and classical conditioning, (2) activation of the posterior lobe during several kinds of purely cognitive tests of executive functions (cognitive planning, set-shifting, working memory), language (verbal memory tasks, verb for noun substitution, synonym generation), mental imagery, and sensory discrimination, (3) activation of the vermal region during tests evaluating emotional modulation. Finally, (4) abnormal activation of the cerebellar vermis and posterior lobe has been observed in several primary psychiatric disorders, most notably schizophrenia, autism, and dyslexia, further discussed below.
The extended coordinating and predicting action of the cerebellum
The cerebellum is assumed to contribute to sensory-motor processing in an automatic manner. After having received, analyzed, and recognized a sensory or a motor pattern (as a prediction of a future sensory state), the cerebellum produces gain and phase corrections that make it possible to regulate the force and activation of large sets of muscles5
. The predicted and actual patterns are then compared; this is followed by the provision of appropriate correction sand thus the generation of movement coordination
. As an extension of this, patterns coming from various cerebro-cortical areas can be processed, allowing the “coordination” of higher cognitive functions. Once activated, the CTCC loops could be used not just for automatic
but also for controlled
functions. These can be set in the more general framework of cognitive control
and executive function6
The cerebellum may take part in cognitive control
by regulating executive functions, which it could do by manipulating different “objects.” These can be considered parts of a set of virtual representations, given that they may be purely symbolic (e.g., thoughts) or applied to symbolic expression (e.g., speech) or voluntary movement (which, after all, is based on a virtual representation of its sensory consequences—see above). The cerebellum then integrates these multiple internal representations (of a motor, sensory, or cognitive/emotional nature) with external stimuli and with voluntary (or self-generated) responses. Indeed, cognitive dysmetria, which is the loss of these functions, is characterized by difficulty in prioritizing, processing, and coordinating responses to incoming information (Andreasen et al., 1996
; Crespo-Facorro et al., 1999
). Importantly, the involvement of the cerebellum in executive functions
becomes more prominent as the complexity of these functions increases (Gottwald et al., 2004
). Deficits in semantic and phonemic fluency and poor performances reported in some memory tasks can be traced back to a deficit in executive functions. Moreover, performance on “basic” attentional tasks (e.g., Go/NoGo) is substantially normal, but performance on “high level” attentional tasks (e.g., the “divided attention” paradigm, where subjects have to respond simultaneously to multiple cognitive tasks) is impaired (Baddeley et al., 1984
; Craik et al., 1996
). Finally, patients with right-sided lesions are more impaired than those with left-sided lesions. This supports the idea of lateralization of cerebellar functions, with verbal deficits mostly occurring in the presence of right cerebellar lesions and visuospatial deficits tending to occur in left cerebellar lesions. Clearly, this lateralization replicates the division of cognitive competences between the two cerebral hemispheres, with which the cerebellum is cross-connected via the pontine nuclei and thalamus.
A similar role of the cerebellum in prioritizing, processing, and coordinating responses to incoming information could underlie cerebellar control of emotional experience7
. Lesions of the cerebellum interfere with affective expectations from a given behavioral context. This is evident in fear conditioning paradigms, in which the relationship between a conditioning stimulus and a frightening unconditioned stimulus can be precisely controlled (Sacchetti et al., 2005
). Vermal lesions can decrease reactivity to frightening stimuli, probably by controlling the output to the hypothalamus, amygdala, hippocampus, septal nuclei, and nucleus accumbens. Likewise, neuroimaging studies show that the cerebellum and the anterior cingulate cortex (ACC) are strongly activated when a painful stimulus is expected after a given cue (Ploghaus et al., 2003
). While the cerebellum builds up the expectation of pain, the ACC, which is strongly connected with the cerebellum, plays an important role in several neurocognitive mechanisms capable of modulating pain perception, mainly attention, expectation, and reappraisal (Wiech et al., 2008
). Moreover, the cerebellum, together with the ACC and the insula, is strongly activated when perceiving pain in others (Jackson et al., 2005
), and these same structures (together with the primary and secondary somatosensory cortices, putamen, and thalamus) have been found to show activation that is related to the intensity of pain (Coghill et al., 1999
). Finally, the cerebellum may also regulate the quality of emotional experience (Turner et al., 2007
). Patients with cerebellar stroke report reduced pleasant feelings in response to happiness-evoking stimuli (while unpleasant experience to frightening stimuli was substantially similar to that recorded in controls).
The prefrontal cerebral cortex has classically been considered to be the main station exerting cognitive control and the limbic system cortices to be the ones primarily involved, together with amygdala and hippocampus, in affective control. Infact, signals processed in the cerebral cortex are continuously sent to subcortical structures, including the cerebellum, which then sends back to the cortex signals able to refine and control cerebro-cortical processing. This process resembles the control of movement planning occurring in the sensory-motor CTCC loops (Figure ).
Figure 4 The meta-levels of cerebellar activity. The figure depicts the causal relationships between the functions that the cerebellum is thought to play at different operative levels (meta-levels hypothesis) and between these same functions and brain pathologies. (more ...)
Meta-levels of signal processing in CTCC loops
So far we have considered observations suggesting that the cerebellum, in addition to taking part in sensory-motor control, is also involved in cognitive/emotional functions. These observations are based on evidence of cerebellar activation during specific cognitive/emotional tasks and on the existence of connections between the cerebellum and relevant cerebro-cortical areas. Moreover, we have tried to make sense of all this by setting cerebellar activity within the general framework of brain functioning and cognitive control. But the question, now, is how can the cerebellum support these multiple operations? The basic hypothesis is that the cerebellum uses, throughout, the same circuit structure, and that different outcomes depend on the specific connections to different brain areas. This also implies that the same code is used for all the operations involving the cerebellum and that motor control and cognition/emotion have an equivalent structure at the level of spike coding.
On an operational level, in order to connect basic circuit functions with cognitive/emotional and mental processing, a series of meta-levels needs to be considered. Ideally, it should be possible, first, to demonstrate the connection between neighboring meta-levels, and thereafter to link the cellular/molecular mechanisms with cognitive/emotional processing and then with mental function and dysfunction.
- Cellular/molecular to circuit. As regards the relationship between the cellular-molecular level and the circuit level of cerebellar operations, several specific hypotheses have been advanced, which are currently under investigation and have been discussed elsewhere (D'Angelo, 2011). The idea, basically, is that the cerebellum is able to exploit spike timing, neuronal dynamics and long-term synaptic plasticity in order to process incoming signals in the spatial, temporal, frequency, and phase domains. At circuit level, timing and plasticity in neurons and synapses can implement adaptable signal processing capabilities, which appear to be the prerequisites for the emergence of cerebellar processing (Hansel et al., 2001; D'Angelo and De Zeeuw, 2009). The outcome of circuit operations on cerebellar functions are themselves bound to signal timing and learning, in line with the original main theories of the cerebellum as a timing and learning device (Albus, 1972; Ivry and Keele, 1989). While connecting circuit operations to emergent behaviors is obviously a fundamental step in understanding how the cerebellum operates, cellular/molecular mechanisms pertain to a different realm and will not be covered here (D'Angelo, 2011).
- Processing primitives. At a low-level of complexity, cerebellar circuit computations emerge in the operations of timing, sensory prediction, and sequence learning. These can be tested in simple experimental tasks and, once embedded in appropriate CTCCs and larger brain systems, may be regarded as a basis for explaining more complex sensory-motor cognitive-emotional operations.
- High-level cognitive processing. The outcome of processing primitives, applied to complex behavioral operations and involving multiple interconnected brain areas, could lead to various high-level cognitive operations. These include attention, language, working memory, visuospatial processing, imagery, reasoning, and decision-making.
- Mental processing and psychiatric diseases. At the highest level, cognitive/emotional functions can be integrated into mental processing. Dysfunction of the relative mechanisms emerges through complex pathological manifestations including autism, schizophrenia, depression, and dyslexia.