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.

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.

Structural correlates of motor adaptation deficits in patients with acute focal lesions of the cerebellum.

Studies of cerebellar patients employing modern lesion-symptom mapping techniques have provided valuable insights into the contribution of the cerebellum to motor adaptation. In patients with chronic focal lesions of the cerebellum, the process of adapting reaching movements to force field (FF) and visuomotor rotation (VM) perturbations relies on different anatomical structures located primarily within the territory of the superior hand area. By contrast, results within the territory of the inferior hand area are less consistent. Compensatory mechanisms may have masked the contribution of the inferior hand area. To test this hypothesis, reaching adaptation to FF and VM perturbations was investigated in 24 patients with acute and subacute lesions of the cerebellum. High-resolution magnetic resonance images were acquired to perform voxel-based lesion-symptom mapping (VLSM). VLSM confirmed that distinct and only partially overlapping areas located primarily within the territory of the superior hand area were crucial for adaptation to FF and VM. More specifically, current results add to previous findings that lobule V is of particular importance in FF adaptation, whereas lobule VI plays a more important role in VM adaptation. No clear evidence for a contribution of the inferior hand area to either task was found. Reach adaptation appears to depend primarily on the superior hand area within the cerebellum.

Storage of a naturally acquired conditioned response is impaired in patients with cerebellar degeneration.

Previous findings suggested that the human cerebellum is involved in the acquisition but not the long-term storage of motor associations. The finding of preserved retention in cerebellar patients was fundamentally different from animal studies which show that both acquisition and retention depends on the integrity of the cerebellum. The present study investigated whether retention had been preserved because critical regions of the cerebellum were spared. Visual threat eye-blink responses, that is, the anticipatory closure of the eyes to visual threats, have previously been found to be naturally acquired conditioned responses. Because acquisition is known to take place in very early childhood, visual threat eye-blink responses can be used to test retention in patients with adult onset cerebellar disease. Visual threat eye-blink responses were tested in 19 adult patients with cerebellar degeneration, 27 adult patients with focal cerebellar lesions due to stroke, 24 age-matched control subjects, and 31 younger control subjects. High-resolution structural magnetic resonance images were acquired in patients to perform lesion-symptom mapping. Voxel-based morphometry was performed in patients with cerebellar degeneration, and voxel-based lesion-symptom mapping in patients with focal disease. Visual threat eye-blink responses were found to be significantly reduced in patients with cerebellar degeneration. Visual threat eye-blink responses were also reduced in patients with focal disease, but to a lesser extent. Visual threat eye-blink responses declined with age. In patients with cerebellar degeneration the degree of cerebellar atrophy was positively correlated with the reduction of conditioned responses. Voxel-based morphometry showed that two main regions within the superior and inferior parts of the posterior cerebellar cortex contributed to expression of visual threat eye-blink responses bilaterally. Involvement of the more inferior parts of the posterior lobe was further supported by voxel-based lesion symptom mapping in focal cerebellar patients. The present findings show that the human cerebellar cortex is involved in long-term storage of learned responses.

Validation of a German version of the Cerebellar Cognitive Affective/ Schmahmann Syndrome Scale: preliminary version and study protocol.

BACKGROUND: Traditionally, cerebellar disorders including ataxias have been associated with deficits in motor control and motor learning. Since the 1980's growing evidence has emerged that cerebellar diseases also impede cognitive and affective processes such as executive and linguistic functions, visuospatial abilities and regulation of emotion and affect. This combination of non-motor symptoms has been named Cerebellar Cognitive Affective/ Schmahmann Syndrome (CCAS). To date, diagnosis relies on non-standardized bedside cognitive examination and, if available, detailed neuropsychological test batteries. Recently, a short and easy applicable bedside test (CCAS Scale) has been developed to screen for CCAS. It has been validated in an US-American cohort of adults with cerebellar disorders and healthy controls. As yet, the CCAS Scale has only been available in American English. We present a German version of the scale and the study protocol of its ongoing validation in a German-speaking patient cohort. METHODS: A preliminary German version has been created from the original CCAS Scale using a standardized translation procedure. This version has been pre-tested in cerebellar patients and healthy controls including medical experts and laypersons to ensure that instructions are well understandable, and that no information has been lost or added during translation. This preliminary German version will be validated in a minimum of 65 patients with cerebellar disease and 65 matched healthy controls. We test whether selectivity and sensitivity of the German CCAS Scale is comparable to the original CCAS Scale using the same cut-off values for each of the test items, and the same pass/ fail criteria to determine the presence of CCAS. Furthermore, internal consistency, test-retest and interrater reliability will be evaluated. In addition, construct validity will be tested in a subset of patients and controls in whom detailed neuropsychological testing will be available. Secondary aims will be examination of possible correlations between clinical features (e.g. disease duration, clinical ataxia scores) and CCAS scores. PERSPECTIVE: The overall aim is to deliver a validated bedside test to screen for CCAS in German-speaking patients which can also be used in future natural history and therapeutic trials. STUDY REGISTRATION: The study is registered at the German Clinical Study Register (DRKS-ID: DRKS00016854).

Association of obstructive sleep apnea and stenotic artery disease in ischemic stroke patients.

BACKGROUND AND PURPOSE: Obstructive sleep apnea (OSA) is suspected to be an independent risk factor for atherosclerotic artery disease. The aim of this hospital-based case-control study was to assess the association between OSA and extracranial artery disease (EAD) as well as peripheral artery disease (PAD) in stroke survivors adjusting for potential confounders. METHODS: Out of 395 stroke survivors in reconvalescent phase, 235 (male 165, female 70, mean age 64.3 years, standard deviation 10.8 years) were retrospectively examined for the presence of OSA as well as EAD. Statistical analyses were then performed to detect correlations between the presence of medium to high degree artery disease (extracranial stenosis equal or higher than 50%: n=67) and the presence of severe OSA (n=58). Adjustments were made for sex, age, Barthel index and concomitant risk factors as well as body mass index and presence of dysarthria or dysphagia. Additionally, the presence of PAD (Fontaine IIa and higher: n=20) was retrospectively examined in 240 out of 395 patients. RESULTS: Severe OSA was associated independently with EAD (OR=2.0, 95%CI 1.0-4.1) and with PAD (OR=6.7, 95%CI 2.1-21.0). EAD additionally showed a stronger association with hypertension and hyperlipidemia. PAD additionally showed a strong association with smoking. CONCLUSION: Our results support the hypothesis that OSA is associated with atherosclerosis and may contribute to ischemic stroke and PAD.