Cognitive aspects: sequencing, behavior, and executive functions

Handbook of Clinical Neurology, Vol. 154 (3rd series) The Cerebellum: From Embryology to Diagnostic Investigations M. Manto and T.A.G.M. Huisman, Editors https://doi.org/10.1016/B978-0-444-63956-1.00010-2 Copyright © 2018 Elsevier B.V. All rights reserved

Chapter 10

Cognitive aspects: sequencing, behavior, and executive functions MARCO MOLINARI1*, MARCELLA MASCIULLO2, SARA BULGHERONI2,3, STEFANO D’ARRIGO2,3, AND DARIA RIVA2,3 1 Department of Neurorehabilitation, Fondazione Santa Lucia, Rome, Italy 2

Translational Clinical Research Division, Fondazione Santa Lucia, Rome, Italy 3

Carlo Besta Neurological Institute, Milan, Italy

Abstract The question posed today is not whether the cerebellum plays a role in cognition, but instead, how the cerebellum contributes to cognitive processes, even in the developmental age. The central role of the cerebellum in many areas of human abilities, motor as well as cognitive, in childhood as well as in adulthood, is well established but cerebellar basic functioning is still not clear and is much debated. Of particular interest is the changing face of cerebellar influence on motor, higher cognitive, and behavioral functioning when adult and developmental lesions are compared. The idea that the cerebellum might play quite different roles during development and in adulthood has been proposed, and evidence from experimental and clinical literature has been provided, including for sequencing, behavioral aspects, and executive functions Still, more data are needed to fully understand the changes of cerebrocerebellar interactions within the segregated loops which connect cerebrum and cerebellum, not only between childhood and adulthood but also in health and disease.

INTRODUCTION The story of cognition and the cerebellum is long yet at the same time short. Hints of the role of cerebellar processing can be traced back to Luciani’s work (Manni and Petrosini, 1997), but it has only been in the last two decades that the importance of cerebellar structures in cognition has been generally accepted. This has led to a reconsideration of the basic cerebellar operational mode and in the theories of cerebellar functioning sequencing has become particularly suitable to describe cerebellar cognitive processing (Molinari et al., 2008). In this regard, it is now accepted that the cerebellum is involved in various types of implicit/procedural learning (Timmann and Daum, 2007; Ito, 2008). Procedural learning may support new stages of representation throughout cognitive development (Karmiloff-Smith, 1995), and it has been proposed that procedural learning is impaired in several neurodevelopmental disorders, including autism and developmental dyslexia (Ullman, 1997). Indeed, differences in distinct cerebellar regions have been identified

in autism, dyslexia, and attention deficit-hyperactivity disorder (ADHD: Stoodley and Limperopoulus, 2016). From a neural perspective, it has been proposed that the cerebellum may be crucial to the optimization of both structure and function of the developing brain (Wang et al., 2014; Stoodley and Limperopoulus, 2016). Wang et al. (2014) suggested that the cerebellum is involved in setting up the specialization of cortical regions involved in cognitive processes, and hence could have a crucial organizing effect during development. Many groups are generating anatomic, experimental, functional neuroimaging, and clinical data stressing the importance of corticocerebellar interactions in many nonmotor domains, such as cognition, emotion, and affective processing (Schmahmann and Sherman, 1997; Timmann and Daum, 2007). This evidence has increased our understanding of cerebellar functions but the definition of the cerebellar role in the different cognitive domains remains obscure, especially when one considers that the cerebellum has an apparently homogeneous anatomic structure based on microcircuits. Regarding the cerebellum and

*Correspondence to: Marco Molinari, Fondazione Santa Lucia, IRCCS, Via Ardeatina 306, 00179, Rome, Italy. Tel: +39-0651501600, E-mail: [email protected]

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cognition, the complex variety of cognitive functions involved implicates the influence of the cerebellum on the cerebral cortex as the key to understanding basic cerebellar processing (Molinari et al., 2002). Early in cerebellar research, sequence processing was proposed as the basic functional mechanism of the motor (Braitenberg et al., 1997) and cognitive (Molinari et al., 1997) domains. Within this context, it is interesting that cognitive/behavioral effects of cerebellar damage are different according to the time of its occurrence. In the present chapter, we will review the relevant adult and developmental literature, in an attempt to depict similarities and differences of the cognitive cerebellar syndrome in these two scenarios.

EARLY-LIFE CEREBELLAR INJURY AND NEURODEVELOPMENTAL DISORDERS Cerebellar dysfunction is a cerebral correlates of several developmental disorders such as ADHD, autism spectrum disorders (ASD), and developmental dyslexia. Moreover, evidence in other clinical populations, such as very preterm infants following early-life cerebellar injury, infants with cerebellar malformations, and children with cerebellar injury (e.g., pediatric posterior fossa tumors) has shown long-term effects of early cerebellar damage on movement, cognition, and affective regulation (Stoodley, 2016). Thus, to date there is unanimous agreement that the cerebellum plays a role in both movement and cognition. Therefore, the question posed today is not whether the cerebellum plays a role in cognition, but instead, how the cerebellum contributes to specific cognitive processes, even in developmental age (Koziol et al., 2014). The sequence detection hypothesis is proposed to represent cerebellar specificity in recognizing serial events as a sequence, detecting sequence violation and generating internal models that can be used to make predictions in motor and nonmotor domains (Leggio and Molinari, 2015).

Sequencing To our knowledge no study has investigated sequencing as discrete cognitive function in children with cerebellar damage, except those regarding sequence detection in serial reaction time task. It has been demonstrated that the cerebellum has a central role in implicit visuomotor sequence learning, i.e., capacity of recognizing serial events as a sequence and predictive processing underlying the serial reaction time task in adults (Molinari et al., 1997), in children with cerebellar tumors (Quintero-Gallego et al., 2006), and in neurodevelopmental disorders with cerebellar involvement, such as dyslexia (Vicari et al., 2005) or genetic syndromes (Vicari et al., 2001; Bussy et al., 2011).

Consistent data support the possibility of modulating human procedural learning by cerebellar transcranial direct current stimulation both in healthy adults (Torriero et al., 2004; Ferrucci et al., 2013) and in a patient with ischemic damage involving the left cerebellum (Torriero et al., 2007).

Behavior The sequence detection hypothesis may also be useful to understand many neurodevelopmental conditions in which impairments in patterns of information processing and disruption in error signal prediction have advanced, such as ADHD and ASD (Leggio and Molinari, 2015). Affect and behavior dysregulation and disorders of emotional modulation can be considered as central and striking aspects of the cerebellar cognitive affective syndrome (CCAS or Schmahmann syndrome), both in adults (Schmahmann and Sherman, 1998) and children (Levisohn et al., 2000). Neuropsychiatric disturbances have been described in case series and in a group of children with congenital lesions, including cerebellar agenesis, dysplasia, and hypoplasia, and acquired conditions, including cerebellar tumor, stroke, and cerebellitis (Bodranghien et al., 2016). For example, in Joubert syndrome (JS: a genetically heterogeneous ciliopathy, characterized in particular by hypodysplasia of the cerebellar vermis and a distinct hindbrain/midbrain malformation: the so-called molar tooth sign) only a few patients have a Diagnostic and Statistical Manual-oriented psychiatric diagnosis, i.e., oppositional defiant and bipolar disorders, but many show emotional and behavioral problems, regardless of the level of cognitive functioning, as confirmed by a recent study on a large cohort of 76 individuals (Summers et al., 2017). In the 54 JS patients described by Bulgheroni et al. (2016), the internalizing problems (emotional reactivity, withdrawal, inattention, poor tolerance to frustration) were prevalent but there were no autistic-like behaviors, apart from two complex cases with severe intellectual, sensory, and motor disabilities. The range of clinical symptomatology is very heterogeneous and includes distractibility and hyperactivity, impulsiveness, anxiety, dysphoria, ritualistic and stereotypical behaviors, illogical thought, and lack of empathy, as well as disinhibition and irritability to aggression. Schmahmann and colleagues (2007) have proposed clustering these disparate neurobehavioral profiles into five major domains, characterized broadly as disorders of attentional control, emotional control, and social skill sets, as well as ASD and psychosis spectrum disorders. In accordance with dysmetria of thought hypothesis, symptom complexes within each putative domain can be considered as reflecting

COGNITIVE ASPECTS: SEQUENCING, BEHAVIOR, AND EXECUTIVE FUNCTIONS either exaggeration (overshoot, hypermetria) or diminution (hypotonia or hypometria) of responses to the internal or external environment (Schmahmann, 2010). More and more data strongly support the motion that neuropsychiatric diseases and disorders of emotional modulation are related to a malfunction of a widespread neural network, including not only limbic cerebellum (vermis and fastigial nucleus) but also cerebellar posterior interpositus nucleus (Perciavalle et al., 2013) and the olivary system, an alternative pathway to the wellknown corticopontine projection system (Dias-Ferreira et al., 2010). The olivary system is involved in the switch from voluntary to completely automatized behaviors and in skill learning, providing automatic motor surveillance during the performance of actions or sequences of actions in a more precise and accurate manner. These switching mechanisms have practical implications for executive control of behavior influencing adjustment speed and the ability to make transitions in a constantly changing environment. From a clinical point of view, this “switching” circuitry may be dysfunctional in children with neurodevelopmental disorders, i.e., ADHD and ASD, who rely on routine, often to the extent of becoming oppositional, and showing behavioral rigidity, with difficulties in making transitions (Dias-Ferreira et al., 2010). The long-standing support for both structural and functional abnormalities in the cerebellum in autism is to date consistent (see Becker and Stoodley, 2013, for review). In terms of specific structure–function relationships, damage to the posterior vermis is most often associated with behavioral dysregulation. Even our own voxel-based morphometry study showed a correlation between alterations in gray-matter volume in the cerebellum (vermis and crus II) and Autism Diagnostic Interviewcommunication and Autism Diagnostic Observation Schedule-total (communication and interaction) in young children with ASD and intellectual disability (Riva et al., 2013a). Furthermore, social-behavioral deficits are frequent and profound both in children with cerebellar vermis lesions (Riva and Giorgi, 2000) and in very preterm infants with cerebellar damage (Limperopoulos et al., 2007). Surgically induced vermal lesions in children with tumors are associated with a range of neurobehavioral affective and social behavioral alterations, ranging from irritability to an autistic-like picture. It is interesting to illustrate the case of a girl with medulloblastoma who underwent the excision of the lower part of the cerebellar vermis (lobules VI and VII) described by Riva and Giorgi (2000). The postsurgical behavioral picture was characterized by gaze aversion, motor and verbal stereotypes, avoidance of emotional contact, lack of empathy, and poor social skills, suggesting an acquired ASD.

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Executive function Sequencing can be considered as an executive function critical to serial order processing, detection of repeated pattern, and feedforward control. Executive functioning results from the interplay of diverse cortical and subcortical neural systems in which the cerebellum plays a critical role (Riva et al., 2013b). Verbal fluency and visual and auditory sequential memory are usually impaired in children and adolescents with acquired cerebellar damage, such as viral inflammatory lesion or tumors (for a review, see Steinlin, 2008). The 4-year and 2-month-old girl with severe viral inflammatory lesion localized in the cerebellum (cerebellitis) showed preserved intelligence but specific sequencing deficit in both cognitive (auditory and visual sequential memory) and daily activities, such as playing by preestablished rules or finding strategic solutions (i.e., Porteus mazes) (Riva, 1998). Mutism disappeared after about 2 weeks from acute onset, and then evolved into telegraphic speech with frequent omissions of functional words and poor verbal initiative. After 3 months, the speech was not dysarthric but aphonic and aprosodic. She produced very simple and incomplete sentences in both spontaneous and constrained situations. No deficits emerged in language comprehension, naming, and sentence repetition, but verbal fluency was very poor in free condition while it was normal when sematic cues were presented. Levisohn et al. (2000) documented CCAS after cerebellar tumor resection in 19 children between 3 and 14 years of age. The syndrome was apparent from visuospatial difficulties, poor verbal initiative, impaired verbal fluency, and story retrieval, as well as deficits in sequential memory, planning, and maintaining set. Lesions involving the vermis induced deterioration in affect regulation, with irritability, impulsiveness, disinhibition, and emotional reactivity, and a limited capacity for attention and behavior modulation, as described above. Riva and Giorgi (2000) studied 26 children after surgical treatment for left and right cerebellar astrocytoma or vermis medulloblastoma. All of the patients with cerebellar hemispheric involvement showed more perseverative errors on the Wisconsin Card Sorting Test, poor verbal fluency (more evident after right lesions), and impaired visual search efficiency in the cancellation test. In accordance with a side lesion effect, patients with right cerebellar lesions had deficient sequential auditory memory while those with left cerebellar lesions manifested sequential visual memory deficit. Individuals with vermis lesions showed prevalent language and behavioral deficits, as mentioned above. Developmental cerebellar cognitive affective syndrome has also been described in premature infants who suffered

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from cerebellar injury, an important complication of very preterm birth, leading to an early impairment of cerebellar growth affecting long-term neurodevelopment in both motor and nonmotor domains (for a review, see Brossard-Racine et al., 2015). A strong association between cerebellar volumetric growth impairment and cognitive disabilities has been found (Parker et al., 2008), as well as executive dysfunction secondary to cerebellar injury characterized by lower scores at an executive function composite (including processing speed, working memory, set shifting, and visual attention) correlated with cerebellar volume deviation in very-low-birth-weight participants relative to normalbirth-weight subjects (Taylor et al., 2011). Executive dysfunctions characterize also the outcome of children with congenital cerebellar malformations. The incidence of posterior fossa malformations diagnosed during the newborn period is estimated to be 1 out of 5000 live births (Bolduc and Limperopoulos, 2009). Hypoplasia, atrophy, or a global or partial dysplasia is associated with 333 different genetic syndromes, including several metabolic diseases. Congenital cerebellar malformations are associated in particular with neuropsychologic deficits and/or neurodevelopmental disorders, intellectual disability, severe language impairments, and emotional-behavioral problems of varying entities to autistic-like pictures (Riva and Bulgheroni, 2014). The type and extent of cerebral reorganization processes in the presence of malformative lesions are difficult to predict and may possibly account for the variability of clinical phenotypes. Therefore, it is more difficult to identify a defined syndromic picture, just as it is the case with acquired cerebellar lesions (Tavano et al., 2007). The isolated inferior vermian hypoplasia and mega cisterna magna tend to have a positive outcome, while vermian hypoplasia and cerebellar agenesis malformations appear to show a moderate or severe degree of neurodevelopmental delay (Bulgheroni et al., 2015). The behavioral developmental profile of 27 children and adults with congenital malformations confined to the cerebellum showed a pattern of deficits in agreement with the general CCAS profile (Tavano et al., 2007), confirming that malformations of cerebellar hemispheres were associated with selective neuropsychologic deficits in executive functioning, visuospatial and linguistic abilities, while malformations affecting the vermis produced affective and social disorders evolving towards autistic-like pictures. Motor impairments were generally less severe and showed a slow and progressive improvement. The aforementioned sample did not include individuals with JS. A recent multicentric study tried to define the clinical phenotype and neurobehavioral features of

54 JS patients aged 10 months to 29 years (Bulgheroni et al., 2016). The findings emphasized remarkably variable global cognitive functioning with full IQ/general quotient ranging from 32 to 129. Communication skills appeared relatively preserved while the motor domain was the area of greatest vulnerability, in accordance with the involvement of vermis. Although there is no evidence of direct involvement of the right lateral cerebellum, the specific deficit in the arithmetic and coding subtest of the Wechsler scales suggests an impairment of the capacity to provide temporary storage and manipulate information, a typical function of verbal working memory. The poor performance in the coding subtest was interpreted as a difficulty in managing double tasks rather than a motor deficit, since it correlated with digit span but not with the motor quotient of the Vineland Adaptive Behavior Scales (Bulgheroni et al., 2016). No correlation was found between the cerebellar dysfunction related to the involvement of the hindbrain malformation and behavioral data, while a high degree of vermis hypoplasia seems to correlate with worse neurodevelopmental outcome (Poretti et al., 2017).

CEREBELLUM IN ADULTHOOD Sequencing Sequencing is the fundamental ability of acquiring knowledge of the structure of sequences by acting on a sequence of events – incidentally through experience or intentionally through explicit effort. To acquire sequence knowledge it must be recognized whether stimuli are presented in a given order and which are the ordering rules. To this aim, the information on a single stimulus must be kept active in a working-memory system and compared with subsequent stimuli. Furthermore, information on time and space relations among stimuli must be acquired. Once the structure of the sequence has been identified, it is stored for subsequent use. Within this framework, it has been proposed that comparisons among actual input and preceding stimuli, as well as detection of similarities and discordances between predicted and actual sequence, occur within the cerebellum (Molinari et al., 2008). Results of this cerebellar processing would then be funneled to the cortex. If the incoming stimulus corresponds to the predicted one, cerebellar output would be minimal; if a discrepancy – error signal – is detected then the activity in the cerebellum increases and a large area of the cerebral cortex would be alerted, with enhancing neuronal excitability (Fig. 10.1). Using magnetoencephalographic recordings, Tesche and Karhu (2000) demonstrated that cerebellar activity is enhanced after an unpredictable omission is inserted into a regular train of somatosensory stimuli. As a result, no activity is present in the parietal cortex,

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Fig. 10.1. Proposed mechanism of cerebellar sequencing for prediction. Incoming events are continuously monitored in the cerebellar circuits. Relations between events are compared in the cerebellar corticonuclear microcomplex (Ito, 2008) and stored in a working-memory buffer (A). Through the same mechanisms, sequences of new incoming events are compared with previously stored event sequences (B). If a match is recognized (C), then an expectancy of repetition is generated (D). The cerebellar monitoring of the flow of events continues, and as long as the prediction is maintained (E), response anticipation is conveyed, and feedforward control can function smoothly (F). If prediction fails (G), then an error signal is activated by the cerebellar output system (H), and feedforward control is interrupted or corrected. From Pisotta and Molinari (2014).

whereas a notable response develops in the cerebellum. Consequently, it can be argued that the cerebellum detects the absence of a somatosensory stimulus to a greater extent than its presence. This response to the absence of a stimulus can be understood only as an indication that something that is expected does not appear (Ivry, 2000). If a sensory pattern is recognized, it is possible to predict the sequence of events and consequently anticipate each one (Nixon, 2003). Thus, in predicting incoming sensory information, the cerebellum governs the detection of the absence of an expected stimulus and the appearance of an unexpected stimulus. Mismatch negativity (MMN) studies in subjects with cerebellar damage in the somatosensory (Restuccia et al., 2007) or auditory (Moberget et al., 2008) domain have confirmed this hypothesis. MMN is believed to be generated by an automatic cortical change detection process that is activated by differences between current and prior inputs. When the MMN protocol is applied to subjects with cerebellar lesions, the MMN response is absent or abnormal.

In spite of its importance for brain functioning (Pisotta and Molinari, 2014), sequencing is not recognized as a discrete cognitive function. Nevertheless, sequencing abilities have been examined in various fields of cognitive neuroscience. Neuronal circuits that are involved have been investigated, including for frontal/predictive functions (Bubic et al., 2010), spatial hippocampal (Iglói et al., 2010) and cerebellar processing (Leggio et al., 2011). Considering the involvement in prediction of sensory events and the long-standing idea that the cerebellum acts as a comparator, participation of the cerebellum among the brain structures involved in sequencing is conceivable and indeed, early in cerebellar research, sequence processing was proposed as the basic functional mechanism also for cognitive domains (Molinari et al., 1997). So, the sequence detection hypothesis is proposed to represent the cerebellar specificity in the predictive brain and links the multifarious impairments that are reported in patients with cerebellar damage. Indeed, sequencing has been reported as the most affected domain in a large cohort of subjects with focal or degenerative cerebellar

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damage (Tedesco et al., 2011). Moreover, this theoretic model has relevance to our understanding of the pathophysiologic mechanisms in many clinical conditions, such as schizophrenia and autism, in which impairments in patterns of information processing and disruptions in error signal prediction have been incriminated.

Behavior In addition to cognitive and language processes, the cerebellum has been proposed to play roles in regulating behavior. Reports in the 1800s noted deviant and aberrant behaviors in individuals with cerebellar anomalies (Schmahmann, 1991). Later, clinical observers (Cooper, 1978) noted a relationship between cerebellar structural abnormalities and psychosis. Schmahmann and Sherman (1998) in their initial description of CCAS described significant behavioral disruption in 20 patients with cerebellar damage with behaviors ranging from affective changes to disinhibited behaviors. Several authors (Schmahmann, 1991; Bower, 1997; Andreasen and Pierson, 2008) suggested that the cerebellum regulates mental operations in much the same way as it regulates movements. According to Schmahmann (1991), the general function of the cerebellum is to facilitate: actions harmonious with the goal, appropriate to context, and judged accurately and reliably according to the strategies mapped out prior to and during the behaviour. In this view, the cerebellum detects, prevents, and corrects mismatches between intended outcome and perceived outcome of the organism’s interaction with the environment. And more specific to social cognition, Schmahmann also noted that disturbed cerebellar functionality leads to “unpredictability to social and social interaction.” Thus, the cerebellum might be a general modulator to prevent and correct errors of actual movement as well as unobserved thought, and it is doing so for distinct functional processes, including social cognitive functions. The critical role of the cerebellum is perhaps better understood from the perspective of its essential function in constructing internal models of mental processes involving sequencing and planning of action, in order to automate and fine-tune not only voluntary motor processes, but also cognitive processes where event sequences play a role (Ito, 2008; Pisotta and Molinari, 2014). This sequencing role is most evident and prominent in mental reconstructions of autobiographic past, future, or hypothetic events. Thus, to understand observed events and their underlying goal, or to infer traits from a person’s observed behavior, it is imperative that sequences of actions are imagined or interpreted into a meaningful whole. The cerebellum may play

a functional role in this sequencing process during social cognition. One view (Ito, 2008; Pisotta and Molinari, 2014) suggests that such internal models are a copy from the social event implications generated in mentalizing areas in the cerebrum and allow humans to anticipate better action sequences during social interaction in an automatic and intuitive way and to fine-tune these anticipations. Thus, signals from the cerebellum might continuously check whether an anticipated event sequence based on (abstract) social information fits with current behavior. The most appealing data on cerebellar role in behavior derive from psychiatric literature. In particular the interesting adult/childhood comparison can be attempted, analyzing cerebellar role in schizophrenia and in autism. In this context, literature documented that early damage to the cerebellar vermis (even if not the unique lesion) is relevant for the later emergence of neuropsychiatric phenomena in childhood. On the other hand, the cerebellum, understood within the context of our current knowledge of its connections and cellular architecture, provides an interesting alternative for explaining the diverse symptoms of schizophrenia. The role of the cerebellum is probably not primary, in the sense that it is not the sole region that is dysfunctional. Rather, schizophrenia is probably a disease involving the interaction between multiple components in distributed brain circuits. None is necessarily primary; on any given occasion, or during any given task, one may malfunction in a way that affects the whole system, or the interacting combination of multiple regions in distributed circuits (e.g., cortical areas, thalamus, cerebellum) may malfunction. Schizophrenia is a devastating psychiatric disorder characterized by a constellation of symptoms, including hallucinations, delusions, impaired judgment, disorganized speech and behavior, motor disruptions, and negative symptoms (decrease/absence of thoughts, actions, affect). The disorder is associated with impairment in cognitive domains, including memory, learning, and executive function. Although the psychopathology of schizophrenia was described many centuries ago and therapeutic modalities are currently available, the neurobiology and genetics underlying its manifestations remain unclear. Nearly all studies on schizophrenia using functional imaging tools have found abnormalities in cerebellar function along with other brain region abnormalities. A study by Nopoulos et al. (1999) reported that the anterior vermis was smaller in males with schizophrenia compared with healthy controls. In addition, it was found that the volume of the vermis is reduced in neurolepticnaıve male patients with schizophrenia. In line with these findings, Loeber et al. (2001) reported that schizophrenic patients exhibited a smaller

COGNITIVE ASPECTS: SEQUENCING, BEHAVIOR, AND EXECUTIVE FUNCTIONS inferior vermis volume compared with controls, and the volume of the anterior vermis and posterior vermis was reduced in drug-naıve patients with first-episode schizophrenia. Smaller volumes of the posterior superior vermis have also been associated with poorer cognitive cluster scores in schizophrenic patients (Okugawa et al., 2007). In addition, schizophrenic patients exhibit volume reductions in the posterior superior vermis. Joyal et al. (2004) reported that 28 male patients with schizophrenia showed volume reductions in the vermis and midsagittal vermal areas as compared with 26 healthy male controls, and Gaser et al. (1999) reported that schizophrenic patients exhibited a volume reduction in the left cerebellum. However, findings of cerebellum volume changes in schizophrenia have not been entirely consistent. For instance, Levitt et al. (1999) reported that the volume of the vermis was increased in patients with schizophrenia when compared with controls. The increase in vermis white-matter volume was found to be significantly correlated with the severity of positive symptoms and cognitive disruption, as well as impairments in verbal logic memory. In addition, schizophrenic patients showed a trend toward greater cerebellar hemispheric volume asymmetry (Levitt et al., 1999). A number of studies examining the relationship between anatomic volume abnormalities and behavioral symptoms of schizophrenia have provided further evidence for a link between cerebellar volume and the disorder. Ichimiya et al. (2001) reported a correlation between vermal volume and total Brief Psychotic Rating Scale subscores in patients with schizophrenia. In agreement with this finding, a study by Yoshihara et al. (2008) reported a positive correlation between negative symptom scores and the volume of white matter in the vermis in schizophrenic patients. Furthermore, some literature data have related memory dysfunctions to the volume of gray matter in the cerebellar hemispheres and the vermis in schizophrenic patients. Dysfunctions of cognitive flexibility are thought to be correlated with reductions in white-matter volume in the cerebellum, and some findings indicate a contribution of cerebellar gray- and white-matter deficits to symptoms of executive dysfunction in schizophrenia (Segarra et al., 2008). Szeszko et al. (2003) reported that normal associations between cerebellar volume and cognitive function were absent in first-episode schizophrenic patients. Taken together, the findings discussed above suggest that the volume of several cerebellar structures is reduced in schizophrenia, and that this volume reduction may be associated with positive, negative, and cognitive symptoms. Many clinical and experimental findings indicate that patients who suffer from schizophrenia are able to estimate

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time less accurately than healthy subjects (Giersch et al., 2016). In addition to attention deficits, schizophrenia is associated with the impairment of working memory (Cohen et al., 1997). However, studies of episodic memory have suggested that patients who suffer from schizophrenia can remember that an event occurred, but do not know when it occurred. These results indicate that patients do not lose memory, but experience a disorganization of time perception (Carroll et al., 2008; Capa et al., 2014). Thus, to better understand the changes that emerge as a result of schizophrenia, many researchers have assessed time perception (Giersch et al., 2016) due to the relationship between schizophrenia and time perception brain regions, pointing out that schizophrenia can be related to change in time processing (Cohen et al., 1997). On the other hand, a theory has been put forward: psychotic symptoms may arise from the loss of internal coherence between internally perceived and externally generated signals (D’Angelo et al., 2013) This “mind–world synchronization” can be achieved only if the perceptual systems constantly tune themselves to an ever-changing environment (Paquette et al., 2013) and the perceptual tuning can be achieved only if patterns are detected and predictions are made (Molinari et al., 2008). Following an early proposal by Braitenberg and colleagues (1997), we applied a “sequence detection model” to describe the operational mode of cerebellar processing in several domains, including emotion processing (Molinari et al., 2008). According to this model, the cerebellum detects and simulates repetitive patterns of temporally or spatially structured events, allowing internal models to be created (Ito, 2008) and predictions about the incoming events to be built (Leggio and Molinari, 2015). Cerebellar contribution to proactive and flexible control of behavior (Miall, 1998; Schlerf et al., 2012) could be achieved by implementing a forward model of the incoming sensory input (Wolpert et al., 1998), thus influencing corticosubcortical circuits implicated in error processing and corrective behavior (Falkenstein et al., 2000, 2001; Beste et al., 2006; Ullsperger and von Cramon, 2006). It is worth noting that, besides schizophrenia, cerebellar dysfunctions have been identified in several other psychiatric pathologies in which impairments in pattern processing and error signal prediction have been advanced. We have advanced the hypothesis that cerebellar atrophy might be the cause of erroneous cerebellar predictions (Pisotta and Molinari, 2014). Altered cerebellar processing would insert virtual errors into the forward control models, inducing continuous correction of the ongoing motor command. This assumption could be translated in schizophrenia in which an error signal could misguide a sequence/pattern of behavior during the adaptation of behavior to context. The presence of schizophrenia

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or schizophrenic symptoms in some forms of degenerative ataxias, such as spinocerebellar ataxias (SCAs), supports our theory. In this regard, literature data documented that SCAs are increasingly associated with some form of psychiatric and neurobehavioral dysfunction; in particular, SCA1 (Joo et al., 1999), SCA2 (Rottnek et al., 2008), and SCA10 (Wexler and Fogel, 2011; Trikamji et al., 2015), have been reported to co-present with major forms of psychosis. In these cases, cerebellar dysfunction may account for psychiatric symptoms. In addition to the disorders of motor coordination and eye movements classically associated with cerebellar dysfunction, cerebellar abnormalities have been implicated in psychiatric disorders, including psychosis (Andreasen et al., 1999; Schmahmann, 2004). Taken together, the data reviewed here indicate that the forward model of cerebellar computing has to be applied also to the behavioral domain and its impairment has to be considered in addressing the cerebellar role in behavioral-related disorders such as schizophrenia. Although distinctly connected with function-specific input and networks, the cerebellum might play a more common basic role in acquiring and predicting motor and cognitive sequences which underlie not only the understanding of planned and observed actions, but also the construction of internal mental models about current events, traits (abstracted out of events), and past, counterfactual, or future autobiographic events. This function would be taxed more heavily when imagining novel or complex event sequences. These ideas concerning the role of the cerebellum are admittedly still at an early stage. One obvious avenue for future research is to test the idea that sequencing is an important aspect of the cerebellar function also in social cognition.

Executive functions As mentioned above, studies investigating corticocerebellar connections support roles of the cerebellum in cognitive functions. Magnetic resonance imaging (MRI) data based on functional studies have revealed cerebellar activation during numerous cognitive tasks. One of the more consistent processes associated with cerebellar activation involves tasks related to working memory or executive function (Desmond and Fiez, 1998; Chen and Desmond, 2005; Hayter et al., 2007; Durisko and Fiez, 2010; Marvel and Desmond, 2010; Pope, 2015). Moreover, cerebellar activation has also been identified with tasks based on attention and timing (Akshoomoff and Courchesne, 1992; Kim et al., 1994; Salman, 2002; Xu et al., 2006). As with the cerebellar role in language, studies on a cerebellar contribution to cognition largely support a role for the lateral cerebellar hemispheres in supporting cognitive processes (Stoodley

and Schmahmann, 2009). In this regard, preclinical models and individuals with cerebellar lesions also show diverse cognitive deficits: executive function deficits, deficiencies in procedural memory, declarative memory, and associative memory, such as eye blink conditioning, and deficits in timing/attention (Schmahmann and Sherman, 1998; Ravizza et al., 2006; Gerwig et al., 2008; Koziol et al., 2014; Kloth et al., 2015). Executive functions refer to cognitive abilities that enable and drive adaptive, goal-oriented behavior. These include the ability to generate thought and think flexibly, to update and manipulate information mentally, to inhibit what is irrelevant to current goals, to self-monitor, and to plan and adjust behavior as appropriate to the present context (Jurado and Rosselli, 2007). Intact executive functions are critical to the ability to adapt to an ever-changing world, and deficits in executive functioning lead to disproportionate impairment in function and activities of daily living (Cahn-Weiner et al., 2002). Executive abilities evolve over childhood and adolescence, paralleling myelination and synaptogenesis of the frontal lobes (Anderson et al., 2001), and then decline with age in relation to loss of prefrontal function (Buckner, 2004). Since the initial description of a central executive by Baddeley and Hitch in 1974, considerable debate has occurred about whether executive function can be explained by a single mechanism or whether executive abilities are driven by distinct (although related) processes (Baddeley and Hitch, 1974; Miyake et al., 2000; Fisk and Sharp, 2004). From a clinical perspective, the executive functions are conventionally split into specific components that can be differentially affected in individual patients. Four components make distinct clinical contributions: information updating and monitoring (referred as working memory), inhibition of prepotent responses, mental set shifting, and fluency (Baddeley and Hitch, 1974; Miyake et al., 2000; Fisk and Sharp, 2004). Large consensus implicated prefrontal cortex in the corticosubcortical network subserving executive functioning, in particular regarding the ability to inhibit actions and monitor performance (Collette et al., 2005). Of the subcortical structures, beside basal ganglia and thalamus (Monchi et al., 2006), cerebellum has recently gained growing attention (Brunamonti et al., 2014; Olivito et al., 2017). Research on patients with cerebellar lesions confirms the role of the cerebellum in the fulfillment of particular executive functions. The data come from neuropsychologic analyses of case studies, observations of selective deficits carried out on small groups of patients, or extensive intergroup comparisons. Some research findings show mild neuropsychologic impairment in the group of patients analyzed (Malm et al., 1998). Patients who underwent neurosurgical procedures on the cerebellum may exhibit profound neuropsychologic

COGNITIVE ASPECTS: SEQUENCING, BEHAVIOR, AND EXECUTIVE FUNCTIONS dysfunction (Schmahmann and Sherman, 1998; Kalashnikova et al., 2005). D’aes and Mariën (2015) have analyzed 75 case studies published since 1981. A variety of executive deficits and working-memory disorders were found in 19 patients. Most comparative studies report on the existence of deficits within various aspects of executive function in patients with either lesions or atrophy of the cerebellum. At the same time, there is considerable variation in patients’ results depending on the study and neuropsychologic tests applied. Some studies confirm deficits in mental flexibility assessed by means of Verbal Fluency Test and Trail Making Test, verbal inhibition of the dominant reaction measured with the Stroop Color Word Test, and problem-solving deficits revealed in the performance of the Wisconsin Card Sorting Test or its modified version. Interesting results are also provided in the study by Lang and Bastian (2002), in which the authors demonstrated deficits in multitasking (effective coordination of different sensory inputs or behavioral outputs). Similarly, certain deficits in working memory have been found in patients with a damaged cerebellum. However, it should be noted that these deficits were rather mild. Ravizza et al. (2006) demonstrated that patients’ performance of the Digit Span test, although within a population norm, was significantly worse compared with the control group. In addition, patients exhibited verbal-memory deficits, with no impairment observed within nonverbal memory. In a study by Neau et al. (2000), patients had significantly lower scores on the Paced Auditory Serial Addition Test. Schmahmann and Sherman (1998) demonstrated the presence of executive function deficits in the form of problems in the areas of planning, set shifting, and working memory in patients with cerebellar pathology. Bellebaum and Daum (2007) noted that, despite the fact that other studies seem to have confirmed executive and cognitive deficits in patients with a damaged cerebellum, the interpretation of these results should be made very cautiously, because the location of the damage and test results differ greatly across individual patients. Also the functional MRI studies of healthy subjects provide further evidence of the involvement of the cerebellum in executive processes, as they demonstrate the activation of this structure in the performance of tasks involving top-down attention (Kellermann et al., 2012), verbal working memory (Marvel and Desmond, 2012; Stoodley et al., 2012), the processes of cognitive inhibition (Rubia et al., 2007; Strick et al., 2009; Brunamonti et al., 2014), verbal fluency (Hubrich-Ungureanu et al., 2002; Frings et al., 2006), and executive functions and decision-making processes (Nagahama et al., 1996; Vorhold et al., 2007). Courchesne and Allen (1997) established that the cerebellum is responsible for preparation of neural

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activity for new stimuli, optimization of their processing, and readiness to react, and, consequently, its damage does not eliminate executive functions, but rather weakens them. According to our previous report (Molinari et al., 1997, Brunamonti et al., 2014), the severity of cerebellar patients’ difficulty in the serial reaction time task in detecting a visuospatial sequence indicates a prevalent role of cerebellar circuitry in recognizing event sequences, rather than in planning and executing them. Therefore, considering the involvement in prediction of sensory events and the long-standing idea that the cerebellum acts as a comparator, the sequence processing was also proposed in executive domains as the basic functional mechanism of cerebellum (Molinari et al., 1997; Brunamonti et al., 2014).

CONCLUSIONS There is unanimous agreement that the cerebellum plays a role in both movement and cognition (Koziol et al., 2014) and the sequences detection hypothesis is an interesting proposal to understand how the cerebellum contributes to cognitive processes (Leggio and Molinari, 2015). The cerebellum plays a critical role in behavior control, which is the essence of “executive function,” considered as the evolutionary advantage conferred by being able to anticipate behavior with both implicit and explicit mechanisms. Cerebellar circuitry is likely involved in procedural (skill) learning and contributes to the acquisition of declarative, semantic knowledge (Koziol et al., 2012). Early disruption of the cerebellum due to preterm birth, prenatal cerebellar developmental lesions (i.e., malformations), cerebellar posterior fossa tumors in early childhood, or developmental disorders seems to cause significant, long-lasting, and wide-ranging changes in the structure and function of cerebrocerebellar systems, with long-term effects on behavior. Early cerebellar damage is often associated with poorer outcomes than cerebellar damage in adulthood. Wang and colleagues (2014) introduced the concept of “developmental diaschisis” to emphasize the importance, particularly during development, of cerebellar modulatory effects on the structure and function of cortical and subcortical areas to which it is closely connected. Neuroimaging studies indicate that early cerebellar injury resulting from preterm birth (Limperopoulos et al., 2014), cerebellar malformations (Bolduc et al., 2011), or tumor resection (Moberget et al., 2015) may adversely impact the development of both cerebrocerebellar white-matter pathways and gray-matter volume of distal regions of the cerebral areas to which the cerebellum projects. From a functional point of view, the potential importance of the cerebellum

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during early development might be explained by a role in building internal models of behavior during implicit/ procedural learning of motor, cognitive, and behavioral information (Ito, 2008). This process drives the optimization of cerebral cortical circuits as skills are acquired and made fluent throughout childhood and into adolescence. The cerebellum instructs frontal systems to think ahead by providing anticipatory control mechanisms on cognitive and affective/emotional behavior (Koziol et al., 2012). Evidence from early-life cerebellar injury and neurodevelopmental disorders also suggests that early cerebellar damage is associated with a range of motor, cognitive, and affective outcomes in a location-dependent manner. For example, vermal damage and malformations have been associated with ASD symptoms (Becker and Stoodley, 2013), while right cerebellar damage has been associated with poorer language outcomes and left cerebellar damage has been associated with poorer visuospatial performance, reflecting the contralateral connections between the cerebellum and the cerebral cortex (Riva and Giorgi, 2000; Scott et al., 2001). However, future research is needed to identify refined structure–function relationships in the developing cerebellum, and specifically to address the impact of fetal/neonatal cerebellar injury on function, using a longitudinal study design (Stoodley and Limperopoulos, 2016). Also for adults, the intriguing aspect of CCAS resulting from cerebellar lesions relies more on clinical differences than on severity of symptomatology. Returning to the cerebellum and sequencing, it would be expected that subjects with cerebellar pathologies perform poorly, independently from the information that is relevant to correctly sort cards. Nevertheless, Leggio et al. (2011) showed different cognitive deficiencies with regard to the etiology and lesion topography. While cerebellar degenerative disorders uniformly affected performance in all modalities of script sequencing (verbal, pictorial, and spatial abstract), focal lesions evoked disparate profiles, depending on the side that was affected. In fact, patients with lesions of the left hemicerebellum performed poorly on script sequences that were based on pictorial material, and patients with lesions in the right hemicerebellum failed to generate script sequences that required verbal elaboration. The presence of right/left and pictorial/verbal differences is consistent with the hypothesis that cerebrocerebellar interactions are organized in segregated and even lateralized corticocerebellar loops, in which specificity is related to the characteristics of the information that is processed, not to the mode of function (Leggio et al., 2011). On the other hand, adults with cerebellar damage show deficits in acquisition of a new skill, but may only show subtle deficits on already-acquired skills that are supported by well-established networks.

Consequently, it can be hypothesized that the cerebellum is maximally involved during the initial stages of learning, and less involved in the retention of learned behaviors. Its role would be more important earlier in life when cerebrocortical networks are first being established, and less important later in life when behaviors have been appropriately set up in distributed cortical networks. Previous data on motor behavior in injured animal models (Petrosini et al., 1990) seem to be in contrast with this hypothesis. In the previous works, the effects of hemicerebellectomy in neonatal rats, compared with the same lesion in adult animals, demonstrated the importance of the “age at lesion” effect with regard to the motor syndrome after having developed cerebellar lesion (Petrosini et al., 1990; Molinari et al., 1997). When hemicerebellectomy is performed at birth, adult rats present slight extensor hypotonia, contralateral to the side of the lesion, and have efficient locomotion. If the same lesion occurs in adulthood, the clinical manifestations are more extensive; the rats show severe extensor hypotonia, ipsilateral to the side of the lesion, which is associated with a wide base and ataxia, impairing locomotion. Moreover, cerebellar agenesis, a condition representing the most severe form in the spectrum of cerebellar disruption, contrasts with the assumption that early cerebellar damage is often associated with poorer outcomes than cerebellar damage in adulthood. In spite of an extraordinary neuroradiologic picture, cerebellar agenesis is a clinical condition compatible with an honorable existence, although somewhat limited (Boltshauser, 2008; Poretti et al., 2009). In these patients, neuropsychologic functioning is quite similar to that observed in subjects who underwent cerebellar hemispheres lesions, showing favorable evolution. Patients may acquire new skills even at an advanced age, despite the severe initial delay. A hypothesis for this progression could be the existence of conscious learning compensatory strategies (based on declarative memory) more closely linked to the functions of the cerebral cortex. In other words, the cerebral cortex in patients affected by cerebellar agenesis may have progressively compensated for those functions normally controlled by the cerebellum (Ullman, 1997). In conclusion, although the central role of the cerebellum in many areas of human abilities, motor as well as cognitive, in childhood as well as in adulthood, is well established, basic cerebellar functioning is still not clear and is much debated. Sequencing and the possible core mechanisms have been hypothesized but other different theories have als been o proposed (Koziol et al., 2012, 2014). Of particular interest is the changing face of cerebellar influence on motor and behavioral abilities when adult and developmental lesions are compared.

COGNITIVE ASPECTS: SEQUENCING, BEHAVIOR, AND EXECUTIVE FUNCTIONS The idea that the cerebellum might play quite different roles during development and in adulthood has been proposed, and evidence from experimental and clinical literature has been reported. Although intriguing, more data are still needed to fully understand the changes occurring within cerebrocerebellar interactions, not only between the childhood and adulthood periods, but also to distinguish between health and disease.

ACKNOWLEDGMENTS This work was partially supported by the Italian Ministry of Health (Ricerca Corrente; to Marco Molinari) and partially by Ricerca Finalizzata of the Italian Ministry of Health (RF-2011-02348213; to Marco Molinari).

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