The CODECS study: COgnitive DEficits in Cerebellar Stroke.

Part of the extra-pyramidal system, the cerebellum is more and more recognized by its non-motor functions known as the cerebellar cognitive affective syndrome. Several studies have identified disturbances specifically in executive and attentional functions after focal cerebellar lesions. However, most studies were performed in small and heterogeneous patient groups. Furthermore, there is a substantial variation in the methodology of assessment. Here, we present the results of a large and homogeneous cohort of patients with isolated uniform cerebellar lesions. After three months post-stroke all patients underwent structural neuroimaging to confirm an isolated lesion and were given neuropsychological testing. The results show that cerebellar lesions relate to mild but long-term cognitive impairment in a broad spectrum of neurocognitive functions compared to normative values. These findings confirm involvement of the cerebellum in cognitive processing and supports the theory of 'dysmetria of thought' based upon uniform cerebellar processing in multiple cognitive domains. This study highlights the following results: 1-Cognitive impairments after isolated cerebellar stroke is confirmed in several cognitive domains. 2-Semantic and phonemic fluency are most affected in cerebellar stroke patients. 3-Verbal deficits show an age-independent long term effect post-stroke and should be studied further in depth. 4-Cognitive disorders after cerebellar stroke are more prominent in women than men.

Differences in hippocampal plasticity and memory outcomes in anterior versus posterior cerebellar stroke.

Neurological symptoms following cerebellar stroke can range from motor to cognitive-affective impairments. Topographic imaging studies from patients with lesions confined to the cerebellum have shown evidence linking anterior cerebellar lobules with motor function and posterior lobules with cognitive function. Damage to the cerebellum can disrupt functional connectivity in cerebellar stroke patients, as it is highly interconnected with forebrain motor and cognitive areas. The hippocampus plays a key role in memory acquisition, a cognitive domain that is negatively impacted by posterior cerebellar stroke, and there is increasing evidence that the cerebellum can affect hippocampal function in health and disease. To study these topographical dissociations, we developed a mouse photo-thrombosis model to produce unilateral strokes in anterior (lobules III-V) or posterior (lobules VI-VIII) cerebellar cortex to examine hippocampal plasticity and behavior. Histological and MRI data demonstrate reproducible injury that is confined to the targeted lobules. We then measured hippocampal long-term potentiation (LTP) ex-vivo with extracellular field recording experiments in acute brain slices obtained from mice 7 days post-cerebellar stroke. Interestingly, we found that a unilateral posterior stroke resulted in a contralateral hippocampal impairment, matching the cerebellothalamic pathway trajectory, while LTP was intact in both hippocampi of mice with anterior strokes. We also assessed motor coordination and memory function at 7 days post-stroke using a balance beam, contextual and delay fear conditioning (CFC and DFC), and novel object recognition (NOR) tasks. Mice with anterior strokes showed lack of coordination evaluated as an increased number of missteps, while mice with posterior strokes did not. Mice with anterior or posterior cerebellar strokes demonstrated similar freezing behavior to shams in CFC and DFC, while only posterior stroke mice displayed a reduced discrimination index in the NOR task. These data suggest that a unilateral LTP impairment observed in mice with posterior strokes produces a mild memory impairment. Our results demonstrate that our model recapitulates aspects of clinical lesion-symptom mapping, with anterior cerebellar strokes producing impaired motor coordination and posterior cerebellar strokes producing an object-recognition memory impairment. Further studies are warranted to interrogate other motor and cognitive-affective behaviors and brain region specific alterations following focal cerebellar stroke. The novel model presented herein will allow for future preclinical translational studies to improve neurological deficits after cerebellar stroke.

Current and Future Perspectives of the Cerebellum in Affective Neuroscience.

The importance of the cerebellum in basic as well as higher order domains of affect processing in the brain has been vividly elaborated and specified by the contributions collected in this book. Indeed, according to increasingly precise research findings in functional neuroimaging and functional neurophysiology, individually delineable areas of the cerebellum play a role in virtually all process levels of the responsible networks of emotion perception, attribution, and experience via a variety of reciprocal connections to the limbic system and distinct areas of the parietal, temporal, and prefrontal cortex. The works in this book identify alternative perspectives in neuroscience research that offer new directions in future investigations. Important aspects will be to pin down the precise cerebellar processes in multiple sensory integration and allocation in cognitive and affective evaluation, and also cognitive-affective as well as motor behavioral responses. In this context, imaging and electrophysiological techniques will highlight the spatial and temporal, and thus the topographic and topological, specificities of the cerebellar areas to the respective networks. In the final chapter, questions and suggestions for future neuroscientific investigations are identified, from whose developments several fields of neurological and psychological disciplines could benefit in order to open up therapeutic avenues for people with cerebellar disorders.

CEREBELLAR COGNITIVE AFFECTIVE SYNDROME IMPROVEMENT WITH SELECTIVE INHIBITOR OF SEROTONIN RECAPTATION.

Cerebellar cognitive affective syndrome (CCAS) is characterized by alterations at the cognitive level (dysexecutive syndrome, visuospatial deficit, language ...), associated with affective / emotional changes.

Double dissociation of single-interval and rhythmic temporal prediction in cerebellar degeneration and Parkinson's disease.

Predicting the timing of upcoming events is critical for successful interaction in a dynamic world, and is recognized as a key computation for attentional orienting. Temporal predictions can be formed when recent events define a rhythmic structure, as well as in aperiodic streams or even in isolation, when a specified interval is known from previous exposure. However, whether predictions in these two contexts are mediated by a common mechanism, or by distinct, context-dependent mechanisms, is highly controversial. Moreover, although the basal ganglia and cerebellum have been linked to temporal processing, the role of these subcortical structures in temporal orienting of attention is unclear. To address these issues, we tested individuals with cerebellar degeneration or Parkinson's disease, with the latter serving as a model of basal ganglia dysfunction, on temporal prediction tasks in the subsecond range. The participants performed a visual detection task in which the onset of the target was predictable, based on either a rhythmic stream of stimuli, or a single interval, specified by two events that occurred within an aperiodic stream. Patients with cerebellar degeneration showed no benefit from single-interval cuing but preserved benefit from rhythm cuing, whereas patients with Parkinson's disease showed no benefit from rhythm cuing but preserved benefit from single-interval cuing. This double dissociation provides causal evidence for functionally nonoverlapping mechanisms of rhythm- and interval-based temporal prediction for attentional orienting, and establishes the separable contributions of the cerebellum and basal ganglia to these functions, suggesting a mechanistic specialization across timing domains.

Extinction of cognitive associations is preserved in patients with cerebellar disease.

In the present study extinction and renewal of cognitive associations were assessed in two experiments in participants with focal and degenerative cerebellar disease. Using a predictive learning task, participants had to learn by trial and error the relationships between food items and the occurrence of stomach trouble in a hypothetical patient. In the first experiment, focus was on renewal effects. Participants with chronic cerebellar stroke (n = 14; mean age 50.9 ± 12 years), participants with degenerative cerebellar disease (n = 16; mean age 58 ± 12 years), age-, sex-, and education matched controls (n = 20; mean age 53.7 ± 10.8 years) and young controls (n = 19; mean age 23.2 ± 2.7 years) were tested. Acquisition and extinction of food-stomach trouble associations took part in two different contexts (represented by restaurants). In a subsequent test phase, food stimuli were presented in both contexts and no feedback was given. This allowed testing for renewal of the initially acquired associations in the acquisition context. Acquisition and extinction learning were not significantly different between groups. Significant renewal effects were present in young controls only. In the second experiment, focus was on extinction. To control for age effects, 19 young participants with chronic surgical lesions of the cerebellum (mean age 25.6 ± 6.1 years), and 24 age-, sex- and education-matched healthy controls were tested. Acquisition and extinction of food-stomach trouble associations took part in the same context. In the extinction phase, the relationship with stomach trouble was reversed in some of the food items. Acquisition and extinction learning were not significantly different between groups. The main finding of the present study was preserved extinction of learned cognitive associations in participants with chronic cerebellar disease. Findings agree with previous observations in the literature that cognitive abnormalities are frequently absent or weak in adults with cerebellar disease. This does not exclude a contribution of the cerebellum to extinction of learned associations. For example, findings may be different in more challenging cognitive tasks, and in participants with acute cerebellar disease with no time for compensation.

Consensus Paper. Cerebellar Reserve: From Cerebellar Physiology to Cerebellar Disorders.

Cerebellar reserve refers to the capacity of the cerebellum to compensate for tissue damage or loss of function resulting from many different etiologies. When the inciting event produces acute focal damage (e.g., stroke, trauma), impaired cerebellar function may be compensated for by other cerebellar areas or by extracerebellar structures (i.e., structural cerebellar reserve). In contrast, when pathological changes compromise cerebellar neuronal integrity gradually leading to cell death (e.g., metabolic and immune-mediated cerebellar ataxias, neurodegenerative ataxias), it is possible that the affected area itself can compensate for the slowly evolving cerebellar lesion (i.e., functional cerebellar reserve). Here, we examine cerebellar reserve from the perspective of the three cornerstones of clinical ataxiology: control of ocular movements, coordination of voluntary axial and appendicular movements, and cognitive functions. Current evidence indicates that cerebellar reserve is potentiated by environmental enrichment through the mechanisms of autophagy and synaptogenesis, suggesting that cerebellar reserve is not rigid or fixed, but exhibits plasticity potentiated by experience. These conclusions have therapeutic implications. During the period when cerebellar reserve is preserved, treatments should be directed at stopping disease progression and/or limiting the pathological process. Simultaneously, cerebellar reserve may be potentiated using multiple approaches. Potentiation of cerebellar reserve may lead to compensation and restoration of function in the setting of cerebellar diseases, and also in disorders primarily of the cerebral hemispheres by enhancing cerebellar mechanisms of action. It therefore appears that cerebellar reserve, and the underlying plasticity of cerebellar microcircuitry that enables it, may be of critical neurobiological importance to a wide range of neurological/neuropsychiatric conditions.

The Cerebellar Cognitive Affective/Schmahmann Syndrome: a Task Force Paper.

Sporadically advocated over the last two centuries, a cerebellar role in cognition and affect has been rigorously established in the past few decades. In the clinical domain, such progress is epitomized by the "cerebellar cognitive affective syndrome" ("CCAS") or "Schmahmann syndrome." Introduced in the late 1990s, CCAS reflects a constellation of cerebellar-induced sequelae, comprising deficits in executive function, visuospatial cognition, emotion-affect, and language, over and above speech. The CCAS thus offers excellent grounds to investigate the functional topography of the cerebellum, and, ultimately, illustrate the precise mechanisms by which the cerebellum modulates cognition and affect. The primary objective of this task force paper is thus to stimulate further research in this area. After providing an up-to-date overview of the fundamental findings on cerebellar neurocognition, the paper substantiates the concept of CCAS with recent evidence from different scientific angles, promotes awareness of the CCAS as a clinical entity, and examines our current insight into the therapeutic options available. The paper finally identifies topics of divergence and outstanding questions for further research.

Prospective investigation of cerebellar cognitive affective syndrome in a previously non-demented population of acute cerebellar stroke.

OBJECTIVE: In this prospective study, we aimed to investigate the presence and evolution of cerebellar cognitive affective syndrome in a cohort of isolated cerebellar stroke with no known cognitive or psychiatric impairment. We tried to distinguish the unconfounded effect of cerebellar lesions on neuropsychological processing. METHODS: After a meticulous exclusion procedure based on possible confounders, we recruited 14 patients and 13 age-matched healthy controls to the study, prospectively. All of the patients had a detailed initial neuropsychological assessment at the first week and a follow-up assessment at the 4th month after stroke. RESULTS: The prevalence of cognitive or behavioral-affective abnormalities in our cohort were 86% and 64% respectively. The patients exhibited mild and transient affective-behavioral abnormalities except for depressive symptoms that persisted in the subacute stage. They scored lower in general cognitive performance as revealed by mini mental test (p=0.001). Memory, executive functions, attention and working memory, central processing speed, and linguistic abilities were impaired (p<0.001; p=0.001; p=0.007; p=0.05; p<0.001 respectively). Improvement was evident only in memory domain of the cognitive functions in the subacute stage. Cognitive impairment was more likely with a medial or posterolateral infarct (p=0.014). Behavioral-affective abnormalities were not associated with a specific location in our cohort. Age seemed to negatively correlate with the recovery in general cognitive performance on the follow-up. CONCLUSIONS: These findings show that acute denervation of cerebellocortical projections leads to mild affective-behavioral abnormalities, and full-blown cerebellar cognitive affective syndrome is rare. However, cognition was significantly affected after an acute cerebellar infarct even in a previously healthy, non-demented pure population.

Extinction and Renewal of Conditioned Eyeblink Responses in Focal Cerebellar Disease.

Extinction of conditioned aversive responses (CR) has been shown to be context-dependent. The hippocampus and prefrontal cortex are of particular importance. The cerebellum may contribute to context-related processes because of its known connections with the hippocampus and prefrontal cortex. Context dependency of extinction can be demonstrated by the renewal effect. When CR acquisition takes place in context A and is extinguished in context B, renewal refers to the recovery of the CR in context A (A-B-A paradigm). In the present study acquisition, extinction and renewal of classically conditioned eyeblink responses were tested in 18 patients with subacute focal cerebellar lesions and 18 age- and sex-matched healthy controls. Standard delay eyeblink conditioning was performed using an A-B-A paradigm. All cerebellar patients underwent a high-resolution T1-weighted brain MRI scan to perform lesion-symptom mapping. CR acquisition was not significantly different between cerebellar and control participants allowing to draw conclusions on extinction. CR extinction was significantly less in cerebellar patients. Reduction of CR extinction tended to be more likely in patients with lesions in the lateral parts of lobule VI and Crus I. A significant renewal effect was present in controls only. The present data provide further evidence that the cerebellum contributes to extinction of conditioned eyeblink responses. Because acquisition was preserved and extinction took place in another context than acquisition, more lateral parts of the cerebellar hemisphere may contribute to context-related processes. Furthermore, lack of renewal in cerebellar patients suggest a contribution of the cerebellum to context-related processes.

The Cerebellar Cognitive Affective Syndrome-a Meta-analysis.

The cerebellar cognitive affective syndrome (CCAS) was first described by Schmahmann and Sherman in 1998. Despite their clear depiction of the syndrome, it is our experience that the CCAS has not yet found solid ground as a disease entity in routine clinical practice. This made us question the dimension of the CCAS in cerebellar patients. We performed a systematic review of the literature according to the PRISMA guidelines, in order to answer the question whether patients with acquired isolated cerebellar lesions perform significantly worse on neuropsychological testing compared to healthy controls. Studies were selected based on the predefined eligibility criteria and quality assessment. The systematic search resulted in ten studies, mainly observational cohorts consecutively including adult patients with isolated cerebellar lesions. Patients were compared to healthy controls, and neuropsychological investigation was done within one year of diagnosis. Meta-analysis of the twelve tests that were done in two or more studies showed that cerebellar patients perform significantly worse on Phonemic Fluency, Semantic Fluency, Stroop Test (naming, reading and interference), Block Design test and WMS-R visual memory. Cerebellar patients have significant and relevant deficits in the visuospatial, language and executive function domain. This meta-analysis therefore emphasizes the importance of the cerebellar cognitive affective syndrome as described by Schmahmann and Sherman.

Anatomo-functional study of the cerebellum in working memory in children treated for medulloblastoma.

INTRODUCTION: Medulloblastoma is the most common malignant cerebral tumor during childhood, arising in the posterior fossa. Children treated for medulloblastoma often experience working memory (WM) deficits, affecting their quality of life and school performance. The aim of the present study undertaken to describe the cerebellar involvement in WM deficits observed in these children. MATERIAL AND METHODS: 23 healthy children and 11 children treated for medulloblastoma were included into study. All subjects performed a detailed neuropsychological examination, an anatomical and functional MRI. Stimuli were presented to the participants with alternating sensory modality and nature of communication in a block design during functional magnetic resonance imaging acquisitions. Non-parametric tests were used for analyzing neuropsychological and behavioral data. SPM8 and SUIT (Spatially Unbiased Atlas Template) were used for anatomical and functional MRI data analyses. RESULTS: Patients had cerebellar resections mainly located in the left posterior lobe. Patients had significantly reduced intelligence quotient, central executive and visuospatial WM. In healthy children group, fMRI showed activations for non-verbal and visuospatial WM in the left posterior cerebellar lobe. CONCLUSION: This study provides further evidence that left posterior cerebellar lobe plays a critical role in WM. Indeed, lesions of left posterior cerebellar lobe were associated with WM impairment in children treated for cerebellar medulloblastoma. Additionally, fMRI using WM tasks showed activation in the left posterior cerebellar lobe in healthy children. Taken together, these findings may help for improving treatment and rehabilitation of children referred for cerebellar tumor.

Development of a Psychiatric Disorder Linked to Cerebellar Lesions.

Cerebellar dysfunction plays a critical role in neurodevelopmental disorders with long-term behavioral and neuropsychiatric symptoms. A 43-year-old woman with a cerebellum arteriovenous malformation and history of behavioral dysregulation since childhood is described. After the rupture of the cerebellar malformation in adulthood, her behavior morphed into specific psychiatric symptoms and cognitive deficits occurred. The neuropsychological assessment evidenced impaired performance in attention, visuospatial, memory, and language domains. Moreover, psychiatric assessment indicated a borderline personality disorder. Brain MRI examination detected macroscopic abnormalities in the cerebellar posterior lobules VI, VIIa (Crus I), and IX, and in the posterior area of the vermis, regions usually involved in cognitive and emotional processing. The described patient suffered from cognitive and behavioral symptoms that are part of the cerebellar cognitive affective syndrome. This case supports the hypothesis of a cerebellar role in personality disorders emphasizing the importance of also examining the cerebellum in the presence of behavioral disturbances in children and adults.

Effective reinforcement learning following cerebellar damage requires a balance between exploration and motor noise.

Reinforcement and error-based processes are essential for motor learning, with the cerebellum thought to be required only for the error-based mechanism. Here we examined learning and retention of a reaching skill under both processes. Control subjects learned similarly from reinforcement and error-based feedback, but showed much better retention under reinforcement. To apply reinforcement to cerebellar patients, we developed a closed-loop reinforcement schedule in which task difficulty was controlled based on recent performance. This schedule produced substantial learning in cerebellar patients and controls. Cerebellar patients varied in their learning under reinforcement but fully retained what was learned. In contrast, they showed complete lack of retention in error-based learning. We developed a mechanistic model of the reinforcement task and found that learning depended on a balance between exploration variability and motor noise. While the cerebellar and control groups had similar exploration variability, the patients had greater motor noise and hence learned less. Our results suggest that cerebellar damage indirectly impairs reinforcement learning by increasing motor noise, but does not interfere with the reinforcement mechanism itself. Therefore, reinforcement can be used to learn and retain novel skills, but optimal reinforcement learning requires a balance between exploration variability and motor noise.

Cerebellar Contribution to Social Cognition.

Emotion attribution (EA) from faces is key to social cognition, and deficits in perception of emotions from faces underlie neuropsychiatric disorders in which cerebellar pathology is reported. Here, we test the hypothesis that the cerebellum contributes to social cognition through EA from faces. We examined 57 patients with cerebellar disorders and 57 healthy controls. Thirty-one patients had complex cerebrocerebellar disease (complex cerebrocerebellar disease group (CD)); 26 had disease isolated to cerebellum (isolated cerebellar disease group (ID)). EA was measured with the Reading the Mind in the Eyes test (RMET), and informants were administered a novel questionnaire, the Cerebellar Neuropsychiatric Rating Scale (CNRS). EA was impaired in all patients (CD p < 0.001, ID p < 0.001). When analyzed for valence categories, both CD and ID missed more positive and negative stimuli. Positive targets produced the highest deficit (CD p < 0.001, ID p = 0.004). EA impairments correlated with CNRS measures of deficient social skills (p < 0.05) and autism spectrum behaviors (p < 0.005). Patients had difficulties with emotion regulation (CD p < 0.001, ID p < 0.001), autism spectrum behaviors (CD p < 0.049, ID p < 0.001), and psychosis spectrum symptoms (CD p < 0.021, ID p < 0.002). ID informants endorsed deficient social skills (CD p < 0.746, ID p < 0.003) and impaired attention regulation (CD p < 0.144, ID p < 0.001). Within the psychosis spectrum domain, CD patients were worse than controls for lack of empathy (CD p = 0.05; ID p = 0.49). Thus, patients with cerebellar damage were impaired on an EA task associated with deficient social skills and autism spectrum behaviors and experienced psychosocial difficulties on the CNRS. This has relevance for ataxias, the cerebellar cognitive affective/Schmahmann syndrome, and neuropsychiatric disorders with cerebellar pathology.

What part of the cerebellum contributes to a visuospatial working memory task?

Although there is evidence that the cerebellum is involved in working memory (WM), it remains unclear which functions within WM the cerebellum supports and which structures are involved in WM. We tested whether the cerebellum is involved in the filtering of incoming information or in its storage. Using a statistical brain mapping approach in 29 patients with cerebellar ischemic stroke, we found that the cerebellum plays a gatekeeper role, as lesions of the tonsil, the lobus semilunaris inferior, and parts of the vermal pyramid rendered WM susceptible to irrelevant information. We conclude that the cerebellum controls incoming WM information.

Metalinguistic deficits in patients with cerebellar dysfunction: empirical support for the dysmetria of thought theory.

The cerebellar cognitive affective syndrome (CCAS) includes disruption of linguistic processing such as verbal fluency, verbal working memory, grammar, and speech perception. We set out to examine linguistic capabilities in patients with cerebellar lesions to determine which domains are spared and which impaired and to evaluate the underlying cognitive structure of these deficits. Forty-four patients with cerebellar disease were compared to 40 healthy controls on the Oral Sentence Production Test (OSPT) which assesses production of sentences with correct syntactic structure and semantic quality. Twenty-five of these cerebellar patients and 25 controls received the Test of Language Competence-Expanded (TLC-E) that assesses metalinguistic ability. The OSPT failed to reveal differences between patients and controls. In contrast, all cerebellar patients were impaired on each of the four TLC-E subtests. Differences between isolated cerebellar and complex cerebrocerebellar patients were nonsignificant. These results confirm and extend prior observations of the TLC-E in patients with cerebellar lesions and suggest three separate but related language impairments following cerebellar dysfunction: (1) disruption in automatic adjustment of intact grammatical and semantic abilities to a linguistic context in sentence production, (2) disruption in automatic adjustment to a linguistic context in sentence interpretation, and (3) disruption of cognitive processes essential for linguistic skills, such as analysis and sequential logical reasoning. These findings are consistent with the unifying framework of the universal cerebellar transform and the dysmetria of thought theory and provide new insights into the nature of the cognitive impairments in patients with the CCAS.

Developmental cerebellar cognitive affective syndrome in ex-preterm survivors following cerebellar injury.

Cerebellar injury is increasingly recognized as an important complication of very preterm birth. However, the neurodevelopmental consequences of early life cerebellar injury in prematurely born infants have not been well elucidated. We performed a literature search of studies published between 1997 and 2014 describing neurodevelopmental outcomes of preterm infants following direct cerebellar injury or indirect cerebellar injury/underdevelopment. Available data suggests that both direct and indirect mechanisms of cerebellar injury appear to stunt cerebellar growth and adversely affect neurodevelopment. This review also provides important insights into the highly integrated cerebral-cerebellar structural and functional correlates. Finally, this review highlights that early life impairment of cerebellar growth extends far beyond motor impairments and plays a critical, previously underrecognized role in the long-term cognitive, behavioral, and social deficits associated with brain injury among premature infants. These data point to a developmental form of the cerebellar cognitive affective syndrome previously described in adults. Longitudinal prospective studies using serial advanced magnetic resonance imaging techniques are needed to better delineate the full extent of the role of prematurity-related cerebellar injury and topography in the genesis of cognitive, social-behavioral dysfunction.

Insights from ERPs into attention during recovery after cerebellar stroke: a case report.

The role of the cerebellum in cognitive performance and attentional processes is a focus of research in recent years. We investigated the P300 component in a patient with a left posterior cerebellar ischemic stroke during both the acute phase and over 4 weeks of follow-up. After stroke, auditory event-related potentials showed a reduction in P3 amplitude, which appears to improve instead after 4 weeks of follow-up. These event-related potential findings could suggest a specific neural pattern of disruption in selective attention during the discrimination processes of the stimulus following a posterior cerebellar lesion. A recovery is observed in the long term.