Evidence for a link among cognition, language and emotion in cerebellar malformations

Abstract

We compared the neurobehavioral profiles of children with Joubert syndrome (JS participants), a rare autosomal recessive condition characterized on magnetic resonance imaging (MRI) by hypoplasia of the cerebellar vermis and midbrain–hindbrain malformations, and children with malformations confined to the cerebellar vermis and one or both hemispheres (Cerebellar malformations – CM participants). We aimed at investigating the influence of anatomo-clinical similarities (vermian malformation) and differences (intact cerebellar hemispheres vs sparing of the pons, respectively) with respect to cognitive, linguistic and emotional development, assuming as a reference framework the Cerebellar Cognitive Affective Syndrome (CCAS). Results show that severe to moderate mental retardation is infrequent in JS children, while it is present in more than half the sample of CM children. Affect development was generally preserved in JS, in high-functioning CM individuals and also in some of the CM children with moderate mental retardation, which raised questions as to the role of a cerebellar vermis lesion in determining affect disorders. Further, cognitive and linguistic profiles on both intellectual and neuropsychological evaluations provided evidence for distinct patterns of peaks and valleys in the two groups, with JS children being significantly more impaired in language and verbal working memory and CM individuals showing a significant impairment of executive functions and emotional development. The overall evidence provides support for an important role of cerebellar structures per se in shaping emotional, cognitive and linguistic development, when vermian lesions are associated to cerebellar hemispheric lesions. Cerebellar vermis and brainstem lesions instead appear to have a major impact on motor-related skills, including oro-motor abilities and verbal working memory.

Introduction

Since the beginning of the 1980s there has been a growing interest in cerebellar non-motor functions and their role in a neurobehavioral model of higher-order cognition (Ito, 1984, Ito, 1993, Ito, 2002, Ito, 2008, Ivry and Keele, 1989, Leiner et al., 1991, Leiner et al., 1993, Schmahmann, 1991, Schmahmann, 1997, Schmahmann, 2006, Schmahmann and Sherman, 1998). At present, the precise nature of the cerebellar contribution to higher-order information processing is unclear, and experimental and clinical investigations have provided evidence for different theoretical stances that see the cerebellum as an event timing device (Ivry and Keele, 1989, Ivry et al., 2002, Ivry and Spencer, 2004); an active sensory mismatch detection mechanism (Devor, 2000, Bower, 2002); an internal prearticulatory verbal code enhancer (Ackermann et al., 2004); a homeostatic supervisor of on-going performance (Schmahmann, 1996); an internal model encoder (Ito, 2008). However, all these theories share the assumption that the cerebellar function is based on the computational power of the cerebellar unit learning machines, constituted by highly modular and serially repeated complexes of parallel fiber-Purkinje cell synapses, modulated by error-signaling, long-term depression inducing climbing fibers (Ito, 2006). Moreover, the purported cerebellar function should be domain-general and cut across information levels, sensorimotor as well as cognitive, autonomic as well as emotional (Bower, 2002, Schmahmann, 2000, Schmahmann, 2004, Ackermann, 2008, Ito, 2008).

Cerebro-cerebellar connection pathways constitute a prerequisite neuroanatomical basis for cerebellar non-motor functions (Ito, 2008). Important findings to this end have been collected in anatomical studies on non-human primates. Particularly relevant for higher-order cognition and language in humans, in monkeys reciprocal connections have been described between the prefrontal cortex and the cerebellar hemispheres through the dentate nucleus (Middleton and Strick, 1994, Kelly and Strick, 2003), between the anterior cingulate gyrus and both the prefrontal cortex and cerebellar hemispheres (through the pons basalis) (Schmahmann and Pandya, 1989, Schmahmann and Pandya, 1997; Fang et al., 2005), and connections from both the prefrontal cortex and the cerebellar hemispheres to the temporo-parietal association areas (Fang et al., 2005). Further, the cerebellar vermis and flocculonodular lobe appear to be tightly connected to structures involved in different aspects of affect modulation, and specifically basic autonomic functions (Haines and Dietrichs, 1984), emotion (Heath, 1973), and mood (Schmahmann, 2000).

The concept of a “CCAS” has been introduced as a likely candidate for a multidomain nosological picture of cognition and affect deficits in patients with acquired or congenital malformative lesions confined to the cerebellum (Schmahmann and Sherman, 1998, Steinlin et al., 1998, Steinlin et al., 1999, Levisohn et al., 2000; Riva and Giorgi, 2000, Schmahmann, 2004, Paulus et al., 2004, Tavano et al., 2007a, Tavano et al., 2007b, Tavano et al., 2007c). In particular, acquired cerebellar lesions may induce disorders of executive functions, and specifically error-detecting, planning, set-shifting, abstract reasoning, verbal fluency and working memory (Fiez et al., 1992, Grafman et al., 1992, Courchesne et al., 1994a, Fiez, 1996, Desmond et al., 1997, Molinari et al., 1997a, Tanaka et al., 2003, Justus et al., 2005, Ravizza et al., 2006); impaired spatial cognition often associated to distractibility, perseveration and inattention, lack of visuospatial organization and procedural memory deficits, sequencing disorders (Molinari et al., 1997b, Schmahmann and Sherman, 1998, Fabbro et al., 2004, Leggio et al., 2008); speech and language disorders such as dysprosodia, mild agrammatism and mild anomia (Silveri et al., 1993, Molinari et al., 1997a, Molinari et al., 1997b, Fabbro et al., 2004, Justus, 2004, Mariën et al., 2009); personality change with blunting of affect and disinhibited or inappropriate behavior (Courchesne, 1991, Courchesne et al., 1994b, Schmahmann, 2000, Schmahmann, 2004). Overall, a more marked expression of the CCAS was found for posterior lobe lesions. Furthermore, while lesions confined to the cerebellar hemispheres and related output nuclei induced more severe cognitive disorders, vermian lesions were more likely to lead to emotional disorders (Kim et al., 1994, Schmahmann and Sherman, 1998, Mariën et al., 2001, Jansen et al., 2005).

The onset of a CCAS following cerebellar tumor surgery has been described in children (Levisohn et al., 2000, Riva and Giorgi, 2000, Scott et al., 2001, Steinlin et al., 2003), where a consistent pattern of deficits of executive functions, visuospatial abilities, expressive language abilities and verbal memory as well as communicative modulation of emotions has been described. These findings suggest the relevance of a life-span contribution of the cerebellum to the processing of cognition, language and emotions (Steinlin, 2007, Tavano et al., 2007a, Tavano et al., 2007c). In this light, malformative lesions of the cerebellum can be especially informative, since they are likely to cause a major impairment of the cerebellar contribution to cognition, language, affect and their relationships from the earliest developmental stages (Tavano et al., 2007b, Tavano et al., 2007c).

Such a developmental perspective highlights the relevance of three major axes in the study of children with malformative cerebellar lesions: 1) Evolution: how do cognitive, linguistic and emotional behavioral characteristics, considered separately and in their interrelationships, change with time? 2) Affective primitive: are all forms of mental retardation and/or verbal impairment associated with affect disruption? 3) Profile specificity: do cognitive and linguistic deficits, and psychiatric features present with association patterns of peaks and valleys proper to different types of syndromes?

Steinlin et al. (1999) studied 11 adult patients with pure non-progressive congenital ataxia with or without cerebellar hypoplasia. Seven displayed a full intelligence quotient (IQ) from 60 to 92, the remaining four patients obtained a harmonic full IQ between 30 and 49. Thus a first distinction can be made between cerebellar patients who exhibit a generalized severe impairment of higher-order functions and those who may present with mild mental retardation or an average intellectual profile. In the group amenable to testing the authors described marked difficulties in visuospatial and visuoconstructive abilities, and sustained attention, while language abilities and selective attention were within normal limits. Chedda et al. (2002) studied 8 patients (6 children and 2 adults) with cerebellar agenesis and found that the severity of motor, neropsychological and affective deficits correlated with the extension of agenesis. Cognitive deficits affected executive functions (perseveration, disinhibition, and difficulty in abstract reasoning, working memory and verbal fluency) and visuospatial abilities, with disorders of perceptual organization, visuospatial copying and recall. All cases displayed marked prosodic difficulties but expressive language difficulties were limited to two cases. Behavioral disorders included obsessive rituals, failure in understanding social cues, and episodes of psychotic depression in the two adults.

In a recent retrospective study we were able to show that cognitive and affective deficits in patients with cerebellar malformations confined to the cerebellum (CM), both children and adults, are also to be ascribed to the nosological picture of the CCAS (Tavano et al., 2007c), with three important differences:

• Although the initial delay may be marked and generalized, it does not preclude the development of higher-order abilities, even at an advanced age (Tavano et al., 2007a), which does not confirm the general stance that the earlier the influence, the more pronounced the problem (Steinlin, 2007). In such a case, a dysexecutive syndrome with lack of visuospatial organization and memory deficits characterizes the ensuing neurocognitive profile.

• Severe verbal and non-verbal communication deficits, likely to result from affective and behavioral dysregulation following extensive vermian damage, are associated with moderate to severe mental retardation and in some cases lie within the diagnostic limits of the autism spectrum disorder. However, this was true for only a subset of patients, while others displayed a neurocognitive profile consistent with the nosological picture of the CCAS, and among these, we were able to find evidence for a dissociation of language and affect in a patient with vermal malformation who did not present with affect disturbances (Tavano et al., 2007b).

• Specific linguistic impairments characterize both receptive and expressive skills in patients with a positive outcome.

The descriptive flexibility of the CCAS can integrate findings from different types of cerebellar deficits. It also provides a framework of reference that can be used to distinguish between mental retardation as a generalized failure in neurocognitive development, and specific deficits within the neurocognitive profile of the CCAS (Mariën et al., 2008).

In our former study we specifically excluded JS, among others, as we were interested in studying malformations confined to the cerebellum only (Tavano et al., 2007c). JS is an autosomal recessive condition clinically characterized by hypotonia, psychomotor delay, ataxia, and oculomotor apraxia (OMA) (Valente et al., 2008). As a structural pathognomonic sign, JS presents with a set of midbrain–hindbrain abnormalities consisting of deepened interpeduncular fossa with narrow isthmus and upper pons, thickened, elongated and mal-oriented superior cerebellar peduncles, and vermian hypoplasia/aplasia/dysplasia of varying degree, which overall take the appearance of a “molar tooth” sign on axial brain magnetic resonance imaging (MRI) (Maria et al., 1997). It was first described by Joubert and collaborators (Joubert et al., 1968), and mental retardation was defined as a hallmark characteristic. However, recently a combination of molecular genetics and enhanced structural neuroimaging allowed researchers to identify a set of Joubert syndrome related disorders (JSRD), of which classical or pure JS represents but a subtype (Gleeson et al., 2004, Millen and Gleeson, 2008, Valente et al., 2005, Valente et al., 2008). At the same time, neurobehavioral investigations in JS documented the existence of a spectral distribution in cognition, with full IQ ranging from <30 to 85 (Steinlin et al., 1997). Fennell's et al. (1999) brief neuropsychological investigation showed that the majority of patients were not amenable to testing, in some cases due to their very young age, but those who were, displayed impaired verbal working and narrative memory, verbal fluency, visuomotor integration, and fine motor control. Besides, evidence from parents' reports suggested the presence of problems in temperament, hyperactivity, aggressiveness and dependency. Severe motor and oculomotor difficulties can make it hard to assess children with JS aged younger than 5 and may thus lead to an overgeneralization of severe learning disability as a characterizing feature (Hodgkins et al., 2004). Similarly, children with a diagnosis of JS do not appear to present with a specific association to classical autism (Takahashi et al., 2005). However, as has been reported for children with CM (Tavano et al., 2007c), a disordered neurodevelopment of cerebellar vermis may induce dysregulation of affect and an invalidating impairment in speech intelligibility (Harris et al., 1998), which in turn may give rise to severe temper tantrums in children who have otherwise good receptive skills (Hodgkins et al., 2004). Such a change in clinical perspective on JS has provided evidence for impairments in cognition, expressive but not receptive language, and emotion, as well as a developmental trajectory that may present with unexpected capabilities at follow-up after age 5 years.

In this work we compared the neurobehavioral profiles of children with malformations confined to the cerebellum (CM) and children with JS. Specifically, for the CM group we selected children exhibiting hypoplasia affecting the vermis and one or both cerebellar hemispheres. Vermian hypoplastic malformation is a shared feature with JS, which however additionally presents with malformation of pontine and medullary structures, including pons basalis, reticular formation and inferior olivary nuclei (Poretti et al., 2007). Conversely, involvement of the cerebellar hemispheres has not been documented in JS; however, an association of “molar tooth” sign and neocortical polymicrogyria over the sylvian fissure has been observed in some cases (Gleeson et al., 2004). We aimed at verifying the effects of such neuroanatomic differences on neurodevelopment along the three main axes of evolution, affective primitive and cognitive profile specificity.