Exercise training and atrial fibrillation: a systematic review and literature analysis.

OBJECTIVE: There are concerns in maintaining adequate levels of physical activity in patients with atrial fibrillation (AF). This could be related to the type of exercise delivered, different among studies, as the words used to describe it as treatment. We have analysed the state-of-art of the role of the exercise in AF by a mathematical analysis. This analysis documented the connections between topics and updated the available evidence through a systematic review of the current literature. MATERIALS AND METHODS: A literature search was conducted using specific terms for studies published between 2000 and 2019. For the descriptive analysis of the current literature, we used the LExical Network analysed by the Graph THeory (LENGTH) method, while to perform our review we followed the PRISMA statement. Downs and Black Quality Index was also used to assess the quality of studies. The LENGTH approach indicated nonspecific terms as "exercise", "physical" and "activity" as more representative than "rehabilitation" to describe the intervention. RESULTS: The systematic review identified nine studies on 882 patients of moderate (n=4) to good (n=5) quality. Training consisted of a combination of supervised ambulatory and home-based outpatient programs, focused on aerobic elements (endurance and resistance training, walking, treadmill and bicycle ergometer). Significant improvements in 6-minute walking test distance and peak oxygen uptake and in quality of life were obtained, with high adherence to training and no serious/significant adverse events. Only one trial was based on cardiac rehabilitation principles. CONCLUSIONS: Adequate exercise training can get a favourable cardiovascular outcome in patients with AF.

Does the cerebellar sequential theory explain spoken language impairments? A literature review.

During the past decades, converging evidence from clinical, neuroimaging and neuroanatomical studies has demonstrated the key role of the cerebellum in the processing of non-motor aspects of language. Although more is known about the way in which the cerebellum participates in the mechanisms involved in written language, there is ambiguous information on its role in other aspects of language, such as in non-motor aspects of spoken language. Thus, to contribute additional insight into this important issue, in the present work, we review several original scientific papers focusing on the most frequent non-motor spoken language impairments evidenced in patients affected by cerebellar pathology, namely, verbal working memory, grammar processing and verbal fluency impairments. Starting from the collected data, we provide a common interpretation of the spoken language disorders in cerebellar patients, suggesting that sequential processing could be the main mechanism by which the cerebellum participates in these abilities. Indeed, according to the cerebellar sequential theory, spoken language impairments could be due to altered cerebellar function to supervise, synchronize and coordinate the activity of different functional modules, affecting the correct optimization of linguistic processing.

Functional Changes of Mentalizing Network in SCA2 Patients: Novel Insights into Understanding the Social Cerebellum.

In recent years, increasing evidence of the cerebellar role in social cognition has emerged. The cerebellum has been shown to modulate cortical activity of social brain regions serving as a regulator of function-specific mentalizing and mirroring processes. In particular, a mentalizing area in the posterior cerebellum, specifically Crus II, is preferentially recruited for more complex and abstract forms of social processing, together with mentalizing cerebral areas including the dorsal medial prefrontal cortex (dmPFC), the temporo-parietal junction (TPJ), and the precuneus. In the present study, the network-based statistics approach was used to assess functional connectivity (FC) differences within this mentalizing cerebello-cerebral network associated with a specific cerebellar damage. To this aim, patients affected by spinocerebellar ataxia type 2 (SCA2), a neurodegenerative disease specifically affecting regions of the cerebellar cortex, and age-matched healthy subjects have been enrolled. The dmPFC, left and right TPJ, the precuneus, and the cerebellar Crus II were used as regions of interest to construct the mentalizing network to be analyzed and evaluate pairwise functional relations between them. When compared with controls, SCA2 patients showed altered internodal connectivity between dmPFC, left (L-) and right (R-) TPJ, and right posterior cerebellar Crus II.The present results indicate that FC changes affect a function-specific mentalizing network in patients affected by cerebellar damage. In particular, they allow to better clarify functional alteration mechanisms driven by the cerebellar damage associated with SCA2 suggesting that selective cortico-cerebellar functional disconnections may underlie patients' social impairment in domain-specific complex and abstract forms of social functioning.

Structural cerebellar correlates of cognitive functions in spinocerebellar ataxia type 2.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum and characterized by a typical motor syndrome. In addition, the presence of cognitive impairment is now widely acknowledged as a feature of SCA2. Given the extensive connections between the cerebellum and associative cerebral areas, it is reasonable to hypothesize that cerebellar neurodegeneration associated with SCA2 may impact on the cerebellar modulation of the cerebral cortex, thus resulting in functional impairment. The aim of the present study was to investigate and quantitatively map the pattern of cerebellar gray matter (GM) atrophy due to SCA2 neurodegeneration and to correlate that with patients' cognitive performances. Cerebellar GM maps were extracted and compared between SCA2 patients (n = 9) and controls (n = 33) by using voxel-based morphometry. Furthermore, the relationship between cerebellar GM atrophy and neuropsychological scores of the patients was assessed. Specific cerebellar GM regions were found to be affected in patients. Additionally, GM loss in cognitive posterior lobules (VI, Crus I, Crus II, VIIB, IX) correlated with visuospatial, verbal memory and executive tasks, while additional correlations with motor anterior (V) and posterior (VIIIA, VIIIB) lobules were found for the tasks engaging motor and planning components. Our results provide evidence that the SCA2 neurodegenerative process affects the cerebellar cortex and that MRI indices of atrophy in different cerebellar subregions may account for the specificity of cognitive symptomatology observed in patients, as result of a cerebello-cerebral dysregulation.

Low-dose aspirin for primary prevention of cardiovascular events in patients with diabetes: Benefit or risk?

Primary prevention aims to avert the onset of cardiovascular disease (CVD) by targeting its natural causes and risk factors; secondary prevention includes strategies and therapies that address preclinical or clinical evidence of CVD progression. The value of aspirin for primary CVD prevention is controversial because of increased bleeding, which may offset the overall modest benefits in patients with no overt CVD. In contrast, the benefits of aspirin for secondary prevention have been repeatedly and convincingly demonstrated to outweigh the risk of bleeding. Diabetes mellitus is a strong risk factor for cardiovascular events, and has been associated with an increased risk of both first and recurrent atherothrombotic events. Therefore, prevention of CVD, the major cause of mortality in patients with diabetes, is one of the most important therapeutic goals. Although the benefit of low-dose aspirin for secondary prevention of CVD is well established, its role for primary prevention remains inconclusive and controversial in diabetes patients. The benefit of aspirin for patients with CVD clearly exceeds the risk of bleeding, and even though a modest benefit has also been demonstrated in primary prevention, the trade-off for aspirin initiation against the increased risk of intracranial and gastrointestinal bleeding is more uncertain. Thus, aspirin for primary CVD prevention should be highly individualized, based on a benefit-risk ratio assessment for the given patient. In conclusion, the mere presence of diabetes is apparently not enough for aspirin to confer a benefit that clearly outweighs the risk of bleeding, and further evidence to the contrary is now needed.

Microstructural MRI Basis of the Cognitive Functions in Patients with Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum. The particular atrophy pattern results in some typical clinical features mainly including motor deficits. In addition, the presence of cognitive impairments, involving language, visuospatial and executive functions, has been also shown in SCA2 patients and it is now widely accepted as a feature of the disease. The aim of the study is to investigate the microstructural patterns and the anatomo-functional substrate that could account for the cognitive symptomatology observed in SCA2 patients. In the present study, diffusion tensor imaging (DTI) based-tractography was performed to map the main cerebellar white matter (WM) bundles, such as Middle and Superior Cerebellar Peduncles, connecting cerebellum with higher order cerebral regions. Damage-related diffusivity measures were used to determine the pattern of pathological changes of cerebellar WM microstructure in patients affected by SCA2 and correlated with the patients' cognitive scores. Our results provide the first evidence that WM diffusivity is altered in the presence of the cerebellar cortical degeneration associated with SCA2 thus resulting in a cerebello-cerebral dysregulation that may account for the specificity of cognitive symptomatology observed in patients.

Neural substrates of motor and cognitive dysfunctions in SCA2 patients: A network based statistics analysis.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by a progressive cerebellar syndrome, which can be isolated or associated with extracerebellar signs. It has been shown that patients affected by SCA2 present also cognitive impairments and psychiatric symptoms. The cerebellum is known to modulate cortical activity and to contribute to distinct functional networks related to higher-level functions beyond motor control. It is therefore conceivable that one or more networks, rather than isolated regions, may be dysfunctional in cerebellar degenerative diseases and that an abnormal connectivity within specific cerebello-cortical regions might explain the widespread deficits typically observed in patients. In the present study, the network-based statistics (NBS) approach was used to assess differences in functional connectivity between specific cerebellar and cerebral "nodes" in SCA2 patients. Altered inter-nodal connectivity was found between more posterior regions in the cerebellum and regions in the cerebral cortex clearly related to cognition and emotion. Furthermore, more anterior cerebellar lobules showed altered inter-nodal connectivity with motor and somatosensory cerebral regions. The present data suggest that in SCA2 a cerebellar dysfunction affects long-distance cerebral regions and that the clinical symptoms may be specifically related with connectivity changes between motor and non-motor cerebello-cortical nodes.

Consensus Paper: Cerebellum and Emotion.

Over the past three decades, insights into the role of the cerebellum in emotional processing have substantially increased. Indeed, methodological refinements in cerebellar lesion studies and major technological advancements in the field of neuroscience are in particular responsible to an exponential growth of knowledge on the topic. It is timely to review the available data and to critically evaluate the current status of the role of the cerebellum in emotion and related domains. The main aim of this article is to present an overview of current facts and ongoing debates relating to clinical, neuroimaging, and neurophysiological findings on the role of the cerebellum in key aspects of emotion. Experts in the field of cerebellar research discuss the range of cerebellar contributions to emotion in nine topics. Topics include the role of the cerebellum in perception and recognition, forwarding and encoding of emotional information, and the experience and regulation of emotional states in relation to motor, cognitive, and social behaviors. In addition, perspectives including cerebellar involvement in emotional learning, pain, emotional aspects of speech, and neuropsychiatric aspects of the cerebellum in mood disorders are briefly discussed. Results of this consensus paper illustrate how theory and empirical research have converged to produce a composite picture of brain topography, physiology, and function that establishes the role of the cerebellum in many aspects of emotional processing.

Impact of cerebellar atrophy on cortical gray matter and cerebellar peduncles as assessed by voxel-based morphometry and high angular resolution diffusion imaging.

In recent years the cerebellum has been attributed amore important role in higher-level functions than previously believed. We examined a cohort of patients suffering from cerebellar atrophy resulting in ataxia, with two main objectives: first to investigate which regions of the cerebrum were affected by the cerebellar degeneration, and second to assess whether diffusion magnetic resonance imaging (dMRI) metrics within the medial (MCP) and superior cerebellar peduncle (SCP) - namely fractional anisotropy (FA) and radial diffusivity (RD) - could be used as a biomarker in patients with this condition. Structural and dMRI data of seven patients with cerebellar atrophy (2 with spinocerebellar atrophy type 2, 1 with Friedreich's ataxia, 4 with idiopathic cerebellar ataxia) and no visible cortical lesions or cortical atrophy were investigated with Freesurfer and voxel-based morphometry (VBM) of gray matter (GM) as well as MCP and SCP FA maps. Correlations of MCP and SCP mean FA with ataxia scores and subscores were also evaluated. Freesurfer showed that patients had significantly reduced volume of the thalamus, ventral diencephalon and pallidum. VBM also demonstrated significantly lower local GM volumes in patients, notably in the head of the caudate nucleus, posterior cingulate gyrus and orbitofrontal cortex bilaterally, as well as in Broca's area in the left hemisphere, and a significant increase in RD in the MCP and SCP of both hemispheres. A significant correlation was found between MCP mean FA and total ataxia score (R=-0.7, p=0.03), and subscores for kinetic functions (R=-0.74, p=0.03) and oculomotor disorders (R=-0.70, p=0.04). The regions of the cerebrum found to have significantly lower local GM volumes have been described to be involved in higher-level cerebellar functions such as initiation of voluntary movements, emotional control, memory retrieval and general cognition. Our findings corroborate recent research pointing to a more extensive corticocerebellar system than previously thought. The significant difference in the MCP and SCP dMRI metrics between patients and controls as well as the significant correlation with ataxia total score and subscores support the use of dMRI metrics as an imaging biomarker for cerebellar degeneration and ataxia.

Cerebellar sequencing: a trick for predicting the future.

"Looking into the future" well depicts one of the most significant concepts in cognitive neuroscience: the brain is constantly predicting future events. Such directedness toward the future has been recognized to be relevant to and beneficial for many aspects of information processing in humans, such as perception, motor and cognitive control, decision-making, theory of mind, and other cognitive processes. Because one of the most adaptive characteristics of the brain is to correct errors, the ability to look into the future represents the best chance to avoid repeating errors. Within the structures that constitute the "predictive brain," the cerebellum has been proposed to have a central function, based on its ability to generate internal models. We suggested that "sequence detection" is the operational mode of the cerebellum in predictive processing. According to this hypothesis, the cerebellum detects and simulates repetitive patterns of temporally or spatially structured events and generates internal models that can be used to make predictions. Consequently, we demonstrate that the cerebellum recognizes serial events as a sequence, detects a sequence violation, and successfully reconstructs the correct sequence of events. Thus, we hypothesize that pattern detection and prediction and processing of anticipation are cerebellum-specific functions within the brain and that the sequence detection hypothesis links the multifarious impairments that are reported in patients with cerebellar damage. We propose that this cerebellar operational mode can advance our understanding of the pathophysiological mechanisms in various clinical conditions, such as schizophrenia and autism.

Quantification of gray matter changes in the cerebral cortex after isolated cerebellar damage: a voxel-based morphometry study.

There is growing evidence based on behavioral and functional imaging studies about the cerebellar involvement in the modulation of cognitive functions. However, it still remains to be clarified how the cerebellum interacts with brain regions sub-serving different cognitive domains. In this study we used magnetic resonance imaging (MRI) and voxel based morphometry (VBM) to investigate changes of cerebral gray matter (GM) density in 15 patients with a focal cerebellar damage (CD) compared to 15 healthy controls. T2-weighted scans and T1-weighted volumes were collected from each subject. With the exception of the cerebellar lesion, none of the patients showed any additional brain MRI abnormality. T1-volumes were analyzed by voxel-based morphometry. Consistent with their neuropsychological abnormalities, patients with right-CD compared to controls showed a reduction of GM density mainly involving the left frontal, parietal and temporal lobes. Conversely, patients with left-CD did not show any significant neuropsychological or cerebral GM abnormality. The present study indicates that specific GM changes may be detected in patients with isolated CD and cognitive dysfunction. We discuss the findings in terms of cerebellar influence on the neuronal networks involved in higher level functions of the association cortex.

Environmental enrichment mitigates the effects of basal forebrain lesions on cognitive flexibility.

The aim of the present study was to investigate whether basal forebrain lesions were able to impair a task requiring cognitive flexibility abilities and analyzing the effect of the rearing in an enriched environment on such form of flexibility in rats with or without basal forebrain cholinergic lesions. In adult rats reared in enriched or standard conditions of the cholinergic projection to the neocortex damage was inflicted by 192 IgG-saporin injection into Ch4 region of basal forebrain. Their performance was compared with those of intact animals reared in analogous conditions in a four-choice serial learning task which taps flexibility in adapting to changing response rules. The results underlined the crucial role of the basal forebrain in mediating cognitive flexibility behaviors and revealed that the increase in social interactions, cognitive stimulation and physical activity of the rearing in enriched environment attenuated impairments caused by the cholinergic lesion. These findings demonstrate that rearing in an enriched environment can improve the ability to cope with brain damage suffered in adulthood.

Cognitive sequencing impairment in patients with focal or atrophic cerebellar damage.

Although cognitive impairment after cerebellar damage has been widely reported, the mechanisms of cerebro-cerebellar interactions are still a matter of debate. The cerebellum is involved in sequence detection and production in both motor and sensory domains, and sequencing has been proposed as the basic mechanism of cerebellar functioning. Furthermore, it has been suggested that knowledge of sequencing mechanisms may help to define cerebellar predictive control processes. In spite of its recognized importance, cerebellar sequencing has seldom been investigated in cognitive domains. Cognitive sequencing functions are often analysed by means of action/script elaboration. Lesion and activation studies have localized this function in frontal cortex and basal ganglia circuits. The present study is the first to report deficits in script sequencing after cerebellar damage. We employed a card-sequencing test, developed ad hoc, to evaluate the influence of the content to be sequenced. Stimuli consisted of sets of sentences that described actions with a precise logical and temporal sequence (Verbal Factor), sets of cartoon-like drawings that reproduced behavioural sequences (Behavioural Factor) or abstract figures (Spatial Factor). The influence of the lesion characteristics was analysed by grouping patients according to lesion-type (focal or atrophic) and lesion-side (right or left). The results indicated that patients with cerebellar damage present a cognitive sequencing impairment independently of lesion type or localization. A correlation was also shown between lesion side and characteristics of the material to be sequenced. Namely, patients with left lesions perform defectively only on script sequences based on pictorial material and patients with right lesions only on script sequences requiring verbal elaboration. The present data support the hypothesis that sequence processing is the cerebellar mode of operation also in the cognitive domain. In addition, the presence of right/left and pictorial/verbal differences is in agreement with the idea that cerebro-cerebellar interactions are organized in segregated cortico-cerebellar loops in which specificity is not related to the mode of functioning, but to the characteristics of the information processed.

Visuospatial abilities in cerebellar disorders.

BACKGROUND: Cerebellar involvement in spatial data management has been suggested on experimental and clinical grounds. OBJECTIVE: To attempt a specific analysis of visuospatial abilities in a group of subjects with focal or atrophic cerebellar damage. METHODS: Visuospatial performance was tested using the spatial subtests of the WAIS, the Benton line orientation test, and two tests of mental rotation of objects-the Minnesota paper form board test (MIN) and the differential aptitude test (DAT). RESULTS: In the Benton line orientation test, a test of sensory analysis and elementary perception, no deficits were present in subjects with cerebellar damage. In MIN, which analyses the capacity to process bidimensional complex figures mentally, and in the DAT, which is based on mental folding and manipulation of tridimensional stimuli, subjects with cerebellar damage were impaired. CONCLUSIONS: The results indicate that lesions of the cerebellar circuits affect visuospatial ability. The ability to rotate objects mentally is a possible functional substrate of the observed deficits. A comparison between visuospatial performance of subjects with focal right and left cerebellar lesions shows side differences in the characteristics of the visuospatial syndrome. Thus cerebellar influences on spatial cognition appear to act on multiple cognitive modules.