Cerebellar fMRI Activation Increases with Increasing Working Memory Demands.

The aim of the present study was to explore cerebellar contributions to the central executive in n-back working memory tasks using 7-T functional magnetic imaging (fMRI). We hypothesized that cerebellar activation increased with increasing working memory demands. Activations of the cerebellar cortex and dentate nuclei were compared between 0-back (serving as a motor control task), 1-back, and 2-back working memory tasks for both verbal and abstract modalities. A block design was used. Data of 27 participants (mean age 26.6 ± 3.8 years, female/male 12:15) were included in group statistical analysis. We observed that cerebellar cortical activations increased with higher central executive demands in n-back tasks independent of task modality. As confirmed by subtraction analyses, additional bilateral activations following higher executive demands were found primarily in four distinct cerebellar areas: (i) the border region of lobule VI and crus I, (ii) inferior parts of the lateral cerebellum (lobules crus II, VIIb, VIII, IX), (iii) posterior parts of the paravermal cerebellar cortex (lobules VI, crus I, crus II), and (iv) the inferior vermis (lobules VI, VIIb, VIII, IX). Dentate activations were observed for both verbal and abstract modalities. Task-related increases were less robust and detected for the verbal n-back tasks only. These results provide further evidence that the cerebellum participates in an amodal bilateral neuronal network representing the central executive during working memory n-back tasks.

Ageing shows a pattern of cerebellar degeneration analogous, but not equal, to that in patients suffering from cerebellar degenerative disease.

Ageing generally leads to impairments in cognitive function and the ability to execute and learn new movements. While the causes of these impairments are often multi-factorial, integrity of the cerebellum in an elderly population is an important predictive factor of both motor function and cognitive function. A similar association between cerebellar integrity and function is true for cerebellar patients. We set out to investigate the analogies between the pattern of cerebellar degeneration of a healthy ageing population and cerebellar patients. We quantified cerebellar regional volumes by applying voxel-based morphometry (VBM) to a publicly available dataset of MR images obtained in 313 healthy subjects aged between 18 and 96 years and a dataset of MR images of 21 cerebellar patients. We observed considerable overlap in regions with the strongest loss of cerebellar volume in the two datasets. In both datasets, the anterior lobe of the cerebellum (lobules I-V) and parts of the superior cerebellum (primarily lobule VI) showed the strongest degeneration of cerebellar volume. However, the most significant voxels in cerebellar patients were shifted posteriorly (lobule VII) compared to the voxels that degenerate most with age in the healthy population. The results showed a pattern of significant degeneration of the posterior motor region (lobule VIIIb) in both groups, and significant degeneration of lobule IX and X in the healthy population, but not in cerebellar patients. Furthermore, we saw strong volumetric degeneration of functionally defined cerebellar regions associated with cerebral somatomotor function in both groups. Predominance of degeneration in the anterior lobe and lobule VI suggests impairment of motor function in both groups, while we suggest that the posterior shift of degeneration in cerebellar patients would be associated with relatively stronger impairment of higher motor function and cognitive function. Thus, these results may explain the specific symptomology associated with cerebellar degeneration in ageing and in cerebellar patients.

Cerebellar Contribution to Context Processing in Extinction Learning and Recall.

Whereas acquisition of new associations is considered largely independent of the context, context dependency is a hallmark of extinction of the learned associations. The hippocampus and the prefrontal cortex are known to be involved in context processing during extinction learning and recall. Although the cerebellum has known functional and anatomic connections to the hippocampus and the prefrontal cortex, cerebellar contributions to context processing of extinction have rarely been studied. In the present study, we reanalyzed functional brain imaging data (fMRI) of previous work investigating context effects during extinction in a cognitive associative learning paradigm in 28 young and healthy subjects (Lissek et al. Neuroimage. 81:131-3, 2013). In that study, event-related fMRI analysis did not include the cerebellum. The 3 T fMRI dataset was reanalyzed using a spatial normalization method optimized for the cerebellum. Data of seven participants had to be excluded because the cerebellum had not been scanned in full. Cerebellar activation related to context change during extinction learning was most prominent in lobule Crus II bilaterally (p < 0.01, t > 2.53; partially corrected by predetermined cluster size). No significant cerebellar activations were observed related to context change during extinction retrieval. The posterolateral cerebellum appears to contribute to context-related processes during extinction learning, but not (or less) during extinction retrieval. The cerebellum may support context learning during extinction via its connections to the hippocampus. Alternatively, the cerebellum may support the shifting of attention to the context via its known connections to the dorsolateral prefrontal cortex. Because the ventromedial prefrontal cortex (vmPFC) is critically involved in context-related processes during extinction retrieval, and there are no known connections between the cerebellum and the vmPFC, the cerebellum may be less important during extinction recall.

Age effects in storage and extinction of a naturally acquired conditioned eyeblink response.

Acquisition of conditioned eyeblink responses is known to decline with age, and age-related decline has been related to a reduction of cerebellar size and function. The aim of the present study was to investigate age-related effects on storage-related processes and extinction of visual threat eyeblink responses (VTERs), conditioned responses which are naturally acquired in early childhood. Storage and extinction of VTERs were tested in 34 healthy participants with an age range from 21 to 74 years (mean age 41.6±16.3 years). High-resolution structural magnetic resonance images (MRI) were acquired in all subjects. Conventional volumetric measures and voxel-based morphometry (VBM) were performed at the level of the cerebellum. Storage and extinction of VTERs showed a significant age-dependent decline. Likewise, cerebellar volume decreased with age. Storage, but not extinction showed a significant positive correlation with age-dependent reduction of total cerebellar volume. VBM analysis showed that gray matter volume in circumscribed areas of intermediate lobules VI, and Crus I and II bilaterally were positively correlated with VTER storage (p<0.05, FWE corrected). Considering extinction, no significant correlations with gray matter cerebellar volume were observed. The present findings show that reduction of storage of learned eyeblink responses with age is explained at least in part by age-dependent decline of cerebellar function. Future studies need to be performed to better understand which brain areas contribute to age-dependent reduction of extinction.

A 7T fMRI study of cerebellar activation in sequential finger movement tasks.

We investigated whether higher activation of the cerebellar cortex in unpredictable compared to predictable sequential finger movements reflects higher demands in motor response selection or also increases in demands on motor sequencing. Furthermore, we asked the question whether the cerebellar nuclei show a similar or reversed response profile as the cerebellar cortex. Ultra-high-field 7T functional magnetic resonance imaging was performed in nineteen right-handed, healthy young participants. Tasks involved finger tapping of a constant sequence, a random sequence, and with one finger at a time (no sequence). Conditions involved the same number of movements of fingers II-V. The three tasks were accompanied by the activation of the known hand areas within the cerebellar cortex and dentate nuclei. Activation of the cerebellar cortex and the dorsorostral dentate was significantly increased in the random-sequence condition compared to both the constant-sequence and the no-sequence conditions, with no significant difference between the constant-sequence and the no-sequence conditions. Error rate and movement frequency was not significantly different between conditions. Thus, differences between conditions cannot be explained by differences in motor execution. Because no difference was observed between the no-sequence and the constant-sequence conditions, increased cerebellar activation in the random-sequence condition likely reflects increased demands in motor response selection. Co-activation of cerebellar cortex and nuclei may be a consequence of excitatory afferent collaterals to the nuclei, "rebound-firing" of dentate neurons, and/or inhibitory synaptic input from Purkinje cells.

Involvement of the cerebellar cortex and nuclei in verbal and visuospatial working memory: a 7 T fMRI study.

The first aim of the present study was to extend previous findings of similar cerebellar cortical areas being involved in verbal and spatial n-back working memory to the level of the cerebellar nuclei. The second aim was to investigate whether different areas of the cerebellar cortex and nuclei contribute to different working memory tasks (n-back vs. Sternberg tasks). Young and healthy subjects participated in two functional magnetic resonance imaging (fMRI) studies using a 7 T MR scanner with its increased signal-to-noise ratio. One group of subjects (n=21) performed an abstract and a verbal version of an n-back task contrasting a 2-back and 0-back condition. Another group of subjects (n=23) performed an abstract and a verbal version of a Sternberg task contrasting a high load and a low load condition. A block design was used. For image processing of the dentate nuclei, a recently developed region of interest (ROI) driven normalization method of the dentate nuclei was applied (Diedrichsen et al., 2011). Whereas activated areas of the cerebellar cortex and dentate nuclei were not significantly different comparing the abstract and verbal versions of the n-back task, activation in the abstract and verbal Sternberg tasks was significantly different. In both n-back tasks activation was most prominent at the border of lobules VI and Crus I, within lobule VII, and within the more caudal parts of the dentate nucleus bilaterally. In Sternberg tasks the most prominent activations were found in lobule VI extending into Crus I on the right. In the verbal Sternberg task activation was significantly larger within right lobule VI compared to the abstract Sternberg task and compared to the verbal n-back task. Activations of rostral parts of the dentate were most prominent in the verbal Sternberg task, whereas activation of caudal parts predominated in the abstract Sternberg task. On the one hand, the lack of difference between abstract and verbal n-back tasks and the lack of significant lateralization suggest a more general contribution of the cerebellum to working memory regardless of the modality. On the other hand, the focus of activation in right lobule VI in the verbal Sternberg task suggests specific cerebellar contributions to verbal working memory. The verbal Sternberg task emphasizes maintenance of stimuli via phonological rehearsal, whereas central executive demands prevail in n-back tasks. Based on the model of working memory by Baddeley and Hitch (1974), the present results show that different regions of the cerebellum support functions of the central executive system and one of the subsidiary systems, the phonological loop.

Direct visualization of cerebellar nuclei in patients with focal cerebellar lesions and its application for lesion-symptom mapping.

As yet, human cerebellar lesion studies have not taken advantage of direct magnetic resonance imaging (MRI) of the cerebellar nuclei in individual patients. In the present study, susceptibility weighted imaging (SWI) was used to visualize lesions of the dentate nuclei in patients with chronic focal lesions. Fifteen patients with cerebellar lesions either due to stroke or tumor surgery underwent SWI imaging using a 1.5T MRI scanner. Dentate nuclei were seen as hypointensities in all patients. Three of the patients underwent additional SWI imaging at 3T and 7T. Compared to 1.5T, corrugation of the dentate wall was seen with greater precision and the dorsal, iron-poorer part was seen more fully. Lesion-symptom mapping was performed based on the 1.5T MR images. Patients were divided into two groups with and without upper limb ataxia. A region-of-interest-(ROI)-driven normalization technique was used which had initially been developed by Diedrichsen et al. (2011) for functional MRI (fMRI) of the dentate nuclei. Compared to conventional normalization of the cerebellum, overlap of dentate lesions improved and lead to increased sensitivity of lesion-symptom maps. Subtraction analysis revealed that the more dorsal and rostral parts of the dentate nuclei were related to upper limb ataxia. Findings were in good accordance with the dentate hand area shown in recent fMRI studies. These data provide evidence that direct identification of dentate lesions together with the ROI-driven normalization technique allows for improved lesion-symptom mapping at the level of the cerebellar nuclei already at conventional 1.5T MRI field strength.

Imaging the deep cerebellar nuclei: a probabilistic atlas and normalization procedure.

The deep cerebellar nuclei (DCN) are a key element of the cortico-cerebellar loop. Because of their small size and functional diversity, it is difficult to study them using magnetic resonance imaging (MRI). To overcome these difficulties, we present here three related methodological advances. First, we used susceptibility-weighted imaging (SWI) at a high-field strength (7T) to identify the dentate, globose, emboliform and fastigial nucleus in 23 human participants. Due to their high iron content, the DCN are visible as hypo-intensities. Secondly, we generated probabilistic maps of the deep cerebellar nuclei in MNI space using a number of common normalization techniques. These maps can serve as a guide to the average location of the DCN, and are integrated into an existing probabilistic atlas of the human cerebellum (Diedrichsen et al., 2009). The maps also quantify the variability of the anatomical location of the deep cerebellar nuclei after normalization. Our results indicate that existing normalization techniques do not provide satisfactory overlap to analyze the functional specialization within the DCN. We therefore thirdly propose a ROI-driven normalization technique that utilizes both information from a T1-weighted image and the hypo-intensity from a T2*-weighted or SWI image to ensure overlap of the nuclei. These techniques will promote the study of the functional specialization of subregions of the DCN using MRI.

Activation of the dentate nucleus in a verb generation task: A 7T MRI study.

There is increasing evidence of a topographic organization within the human cerebellar cortex for motor and non-motor functions. Likewise, a subdivision of the dentate nucleus in a more dorsal and rostral motor domain and a more ventral and caudal non-motor domain has been proposed by Dum and Strick (2003) based on anatomical studies in monkey. In humans, however, very little is known about topographic organization within the dentate nucleus. Activation of the dentate nucleus in a verb generation task was examined in young and healthy subjects using ultra-highfield 7T functional magnetic resonance imaging (fMRI) with its increase in signal-to-noise ratio. Data of 17 subjects were included in statistical analysis. Subjects were asked to (i) read words (nouns) aloud presented on a screen, (ii) silently read the same nouns, (iii) silently generate the appropriate verbs to the same nouns and (iv) to silently repeat the names of the months. A block design was used. For image processing, a recently developed region of interest (ROI) driven normalization method of the dentate nuclei was applied. Activation related to motor speech (contrast aloud reading minus silent reading) was strongest in the rostral parts of the dentate nucleus. Dorsorostral activations were present bilaterally. Activation related to verb generation (contrast verb generation minus silent reading) was found in the ventrocaudal parts of the dentate nucleus on the right. The present findings are in good accordance with the anatomical data in monkeys and suggest that the human dentate nucleus can be subdivided into a rostral and more dorsal motor domain and a ventrocaudal non-motor domain.

Evidence for a motor and a non-motor domain in the human dentate nucleus--an fMRI study.

Dum and Strick (J. Neurophysiol. 2003; 89, 634-639) proposed a division of the cerebellar dentate nucleus into a "motor" and "non-motor" area based on anatomical data in the monkey. We asked the question whether motor and non-motor domains of the dentate can be found in humans using functional magnetic resonance imaging (fMRI). Therefore dentate activation was compared in motor and cognitive tasks. Young, healthy participants were tested in a 1.5 T MRI scanner. Data from 13 participants were included in the final analysis. A block design was used for the experimental conditions. Finger tapping of different complexities served as motor tasks, while cognitive testing included a verbal working memory and a visuospatial task. To further confirm motor-related dentate activation, a simple finger movement task was tested in a supplementary experiment using ultra-highfield (7 T) fMRI in 23 participants. For image processing, a recently developed region of interest (ROI) driven normalization method of the deep cerebellar nuclei was used. Dorso-rostral dentate nucleus activation was associated with motor function, whereas cognitive tasks led to prominent activation of the caudal nucleus. The visuospatial task evoked activity bilaterally in the caudal dentate nucleus, whereas verbal working memory led to activation predominantly in the right caudal dentate. These findings are consistent with Dum and Strick's anatomical findings in the monkey.

Cerebellar vermis contributes to the extinction of conditioned fear.

The cerebellum is known to contribute to the acquisition and retention of conditioned motor and emotional responses. Eyeblink conditioning and fear conditioning have been studied in greatest detail. Whereas a considerable number of studies have shown that the cerebellum is also involved in extinction of conditioned eyeblink responses, the likely contribution of the cerebellum to extinction of conditioned fear responses has largely been ignored. In the present study, we analyzed functional brain imaging data (fMRI) of previous work investigating extinction of conditioned fear in 32 young and healthy men, in which event-related fMRI analysis did not include the cerebellum. This dataset was analyzed using a spatial normalization method optimized for the cerebellum. During fear acquisition, an unpleasant electric shock (unconditioned stimulus; US) was paired with one of two pictures of geometrical figures (conditioned stimulus; CS+), while the other picture (CS-) was never paired with the US. During extinction, CS+ and CS- were presented without the US. During the acquisition phase, the fMRI signal related to the CS+ was significantly higher in hemispheric lobule VI in early compared to late acquisition (p<.05, permutation corrected). During the extinction phase, the fMRI signal related to the contrast CS+>CS- was significantly higher within the anterior vermis in early compared to late extinction (p<.05, permutation corrected). The present data show that the cerebellum is not only associated with the acquisition but also with the extinction of conditioned fear.

Lesions of the dentate and interposed nuclei are associated with impaired prehension in cerebellar patients.

In a recent study using voxel based lesion symptom mapping (VLSM) in cerebellar patients following stroke we found associations of prehensile deficits to lesions of the cerebellar cortex and dentate nucleus (DN). Associations to lesions of the interposed nucleus (IN), which has been shown to contribute to prehension in monkeys, could not be established. One possible reason was that the IN was largely unaffected in the stroke patients. To further address the question of IN involvement in prehension we performed VLSM in patients with surgical cerebellar lesions (n=20), exhibiting high lesion overlap in the medial and intermediate cerebellum including the IN. Prehensile deficits were quantified by analyses of movement kinematics and finger forces. In the patient population prehensile deficits comprised lower movement velocity in reaching and increased lift-off time in grasping. These were associated with lesions of the intermediate and lateral cerebellar cortex together with their output nuclei. Specifically, IN lesions were linked to increased lift-off time in grasping and not to slower reaching movements. Thus, our data support IN contribution particularly for the fluent production of grip forces during dexterous prehension in humans.

Primary hyperparathyroidism in a schizophrenic women.

This is a case presentation of a 52 year old woman with a past history of schizophrenia who develops an acute psychosis. The point is emphasized that a deterioration in mental state in a patient with schizophrenia should not too readily be attributed to the 'functional' psychosis. Psychiatric patients may present with organic mental disorders requiring medical or surgical intervention. Thus the psychiatrist must always be alert to the possibility of new pathology and examine carefully for signs of organic disturbances. This case turned out to be one of acute hyperparathyroidism cured by surgical removal of an adenoma of the parathyroid gland.