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.

The Yin and Yang of Operating on a Posterior Fossa Meningioma: The Schmahmann Syndrome.

The cerebellum is classically linked with control of motor function, such as coordination, balance, and regulation of movement. There is an increasing awareness, now, of the non-motor functions of the cerebellum, and the occurrence of behavioral anomalies with cerebellar disorders. We present the first report of Schmahmann syndrome (cerebellar cognitive affective syndrome [CCAS]) occurring secondary to posterior fossa meningioma excision. A 35-year-old lady with a posterior fossa meningioma developed an infarct of the right posterosuperior cerebellar hemisphere and ipsilateral superior vermis, following suboccipital craniotomy and tumor resection. Few days after the surgery, she presented with aggressive and emotional behavior, irrelevant talk, and emotional lability. The CCAS scale was administered, and she scored poorly on almost all parameters. A neuropsychological evaluation was also done. The occurrence of CCAS, posterior fossa syndrome (PFS), and behavioral abnormalities like abnormal pathological laughter/crying provides further clinical evidence of the "affective" functions of the cerebellum, modulated mainly by the posterior lobe and vermis of the cerebellum.

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.

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.

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.

Possible affective cognitive cerebellar syndrome in a young patient with COVID-19 CNS vasculopathy and stroke.

Early case series suggest that about one-third of patients with COVID-19 present with neurological manifestations, including cerebrovascular disease, reported in 2%-6% of hospitalised patients. These are generally older patients with severe infection and comorbidities. Here we discuss the case of a previously fit and well 39-year-old man who presented with fever and respiratory symptoms, evolving in pneumonia with hypoxia but only requiring continuous positive airway pressure. After resolution of the respiratory disease, the patient developed focal neurology and was found to have bilateral occipital, thalamic and cerebellar infarcts. A diagnosis of COVID-19 central nervous system vasculopathy was made. He developed a florid neuropsychiatric syndrome, including paranoia, irritability, aggression and disinhibition, requiring treatment with antipsychotics and transfer to neurorehabilitation. Neuropsychometry revealed a wide range of cognitive deficits. The rapid evolution of the illness was matched by fast resolution of the neuropsychiatric picture with mild residual cognitive impairment.

Perioperative Assessment of Cerebellar Masses and the Potential for Cerebellar Cognitive Affective Syndrome.

The cerebellum was long perceived to be a region of limited importance with primary functions in the regulation of motor control. A degree of its functional topography in motor modulation has been traditionally appreciated. However, an evolving body of evidence supports its role in a range of cognitive processes, including executive decision making, language, emotional processing, and working memory. To this end, numerous studies of cerebellar stroke syndromes as well as investigations with functional magnetic resonance imaging and diffusion tensor imaging have given clinicians a better model of the functional topography within the cerebellum and the essential lanes of communication with the cerebrum. With this deeper understanding, neurosurgeons should integrate these domains into the perioperative evaluation and postoperative rehabilitation of patients with cerebellar tumors. This review aims to discuss these understandings and identify valuable tools for implementation into clinical practice.

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 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.

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.

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.

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.

Increasing Motor Noise Impairs Reinforcement Learning in Healthy Individuals.

Motor variability from exploration is crucial for reinforcement learning as it allows the nervous system to find new task solutions. However, motor variability from noise can be detrimental to learning and may underlie slowed reinforcement learning performance observed in individuals with cerebellar damage. Here we examine whether artificially increasing noise in healthy individuals slows reinforcement learning in a manner similar to that seen in patients with cerebellar damage. Participants used binary reinforcement to learn to rotate their reach angle in a series of directions. By comparing task performance between conditions with different levels of added noise, we show that adding a high level of noise-matched to a group of patients with cerebellar damage-slows learning. In additional experiments, we show that the detrimental effect of noise may lie in reinforcing incorrect behavior, rather than not reinforcing correct behavior. By comparing performance between healthy participants with added noise and a group of patients with cerebellar damage, we found that added noise does not slow the learning of the control group to the same degree observed in the patient group. Using a mechanistic model, we show that added noise in the present study matched patients' motor noise and total learning. However, increased exploration in the control group relative to the group with cerebellar damage supports faster learning. Our results suggest that motor noise slows reinforcement learning by impairing the mapping of reward to the correct action and that this may underlie deficits induced by cerebellar damage.

Scales for the clinical evaluation of cerebellar disorders.

Clinical scales represent an important tool not only for the initial grading/scoring of disease and assessment of progression, but also for the quantification of therapeutic effects in clinical trials. There are several scales available for the clinical evaluation of cerebellar symptoms. While some scales have been developed and evaluated for specific cerebellar disorders such as Friedreich ataxia, others reliably capture cerebellar symptoms with no respect to the underlying etiology. Each scale has its strengths and weaknesses. Extensive scales are certainly useful for thorough documentation of specific features of certain phenotypes, but this gain of information is not always essential for the purpose of a study. Therefore, compact and manageable scales like the Scale for the Assessment and Rating of Ataxia (SARA) or Brief Ataxia Rating Scale (BARS) are often preferred compared to more complex scales in observational and therapeutic studies.

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.