Relationships Between Regional Cerebellar Volume and Sensorimotor and Cognitive Function in Young and Older Adults

The cerebellum has been implicated in both sensorimotor and cognitive function, but is known to undergo volumetric declines with advanced age. Individual differences in regional cerebellar volume may therefore provide insight into performance variability across the lifespan, as has been shown with other brain structures and behaviors. Here, we investigated whether there are regional age differences in cerebellar volume in young and older adults, and whether these volumes explain, in part, individual differences in sensorimotor and cognitive task performance. We found that older adults had smaller cerebellar volume than young adults; specifically, lobules in the anterior cerebellum were more impacted by age. Multiple regression analyses for both age groups revealed associations between sensorimotor task performance in several domains (balance, choice reaction time, and timing) and regional cerebellar volume. There were also relationships with working memory, but none with measures of general cognitive or executive function. Follow-up analyses revealed several differential relationships with age between regional volume and sensorimotor performance. These relationships were predominantly selective to cerebellar regions that have been implicated in cognitive functions. Therefore, it may be the cognitive aspects of sensorimotor task performance that are best explained by individual differences in regional cerebellar volumes. In sum, our results demonstrate the importance of regional cerebellar volume with respect to both sensorimotor and cognitive performance, and we provide additional insight into the role of the cerebellum in age-related performance declines.     

How do mammillary body inputs contribute to anterior thalamic function?

It has long been assumed that the main function of the mammillary bodies is to provide a relay for indirect hippocampal inputs to the anterior thalamic nuclei. Such models afford the mammillary bodies no independent role in memory and overlook the importance of their other, non-hippocampal, inputs. This review focuses on recent advances that herald a new understanding of the importance of the mammillary bodies, and their inputs from the limbic midbrain, for anterior thalamic function. It has become apparent that the mammillary bodies’ contribution to memory is not dependent on afferents from the subicular complex. Rather, the ventral tegmental nucleus of Gudden is a vital source of inputs that support memory processes within the medial mammillary bodies. In parallel, the lateral mammillary bodies, via their connections with the dorsal tegmental nucleus of Gudden, are critical for generating head-direction signals. These two parallel, but distinct, information streams converge on the anterior thalamic nuclei and support different aspects of spatial memory.     

Re-evaluating the role of the mammillary bodies in memory

Although the mammillary bodies were among the first brain regions to be implicated in amnesia, the functional importance of this structure for memory has been questioned over the intervening years. Recent patient studies have, however, re-established the mammillary bodies, and their projections to the anterior thalamus via the mammillothalamic tract, as being crucial for recollective memory. Complementary animal research has also made substantial advances in recent years by determining the electrophysiological, neurochemical, anatomical and functional properties of the mammillary bodies. Mammillary body and mammillothalamic tract lesions in rats impair performance on a number of spatial memory tasks and these deficits are consistent with impoverished spatial encoding. The mammillary bodies have traditionally been considered a hippocampal relay which is consistent with the equivalent deficits seen following lesions of the mammillary bodies or their major efferents, the mammillothalamic tract. However, recent findings suggest that the mammillary bodies may have a role in memory that is independent of their hippocampal formation afferents; instead, the ventral tegmental nucleus of Gudden could be providing critical mammillary body inputs needed to support mnemonic processes. Finally, it is now apparent that the medial and lateral mammillary nuclei should be considered separately and initial research indicates that the medial mammillary nucleus is predominantly responsible for the spatial memory deficits following mammillary body lesions in rats.     

White matter fiber tractography and color mapping of the normal human cerebellum with diffusion tensor imaging

Diffusion tensor imaging (DTI) color mapping and fiber tractography was used to study the white matter within the cerebellum along with the afferent and efferent tracts associated with the cerebellum in 24 normal human subjects. The most prominent structures that can be readily identified using these DTI techniques are the middle, inferior and superior cerebellar peduncles. Furthermore DTI shows transverse white matter fiber that cross between the two cerebellar hemispheres at the level of the vermis. At the hemispheric level fibers to the dentate, to the emboliform nuclei are clearly visible on DTI as is the afferent pathway represented by the middle cerebellar peduncle. Selective DTI fiber tractography provides very exquisite images of the cerebellar peduncles and of the fibers projecting to and from the cerebellar cortex. This study demonstrates that DTI is complementary to conventional MRI in that DTI elucidates the orientation of white matter fiber bundles that are associated with the cerebellum. Therefore we anticipate that DTI will become an important adjunct to conventional MRI for clinical and basic studies of cerebellar ataxias and congenital disorders involving the cerebellum and brain stem. This work provides a summary of the normal DTI appearance of the cerebellar white matter which will be useful for interpreting DTI results in clinical populations.     

Cerebellar networks with basal ganglia: feasibility for tracking cerebello‐pallidal and subthalamo‐cerebellar projections in the human brain

Neuroanatomical studies using transneuronal virus tracers in macaque monkeys recently demonstrated that substantial interactions exist between basal ganglia and the cerebellum. To what extent these interactions are present in the human brain remains unclear; however, these connections are thought to provide an important framework for understanding cerebellar contributions to the manifestation of basal ganglia disorders, especially with respect to tremor genesis in movement disorders such as Parkinson's disease. Here, we tested the feasibility of assessing these connections in vivo and non‐invasively in the human brain with diffusion magnetic resonance imaging and tractography. After developing a standardized protocol for manual segmentation of basal ganglia and cerebellar structures, masks for diffusion tractography were defined based on structural magnetic resonance images. We tested intra‐ and inter‐observer stability and carried out tractography for dentato‐pallidal and subthalamo‐cerebellar projections. After robustly achieving connection probabilities per tract, the connectivity values and connectional fingerprints were calculated in a group of healthy volunteers. Probabilistic diffusion tractography was applicable to probe the inter‐connection of the cerebellum and basal ganglia. Our data confirmed that dentato‐thalamo‐striato‐pallidal and subthalamo‐cerebellar connections also exist in the human brain at a level similar to those that were recently suggested by transneuronal tracing studies in non‐human primates. Standardized segmentation protocols made these findings reproducible with high stability. We have demonstrated that diffusion tractography in humans in vivo is capable of revealing the structural bases of cerebellar networks with the basal ganglia. These findings support the role of the cerebellum as a satellite system of established cortico‐basal ganglia networks in humans.     

Distinct critical cerebellar subregions for components of verbal working memory

A role for the cerebellum in cognition has been proposed based on studies suggesting a profile of cognitive deficits due to cerebellar stroke. Such studies are limited in the determination of the detailed organisation of cerebellar subregions that are critical for different aspects of cognition. In this study we examined the correlation between cognitive performance and cerebellar integrity in a specific degeneration of the cerebellar cortex: Spinocerebellar Ataxia type 6 (SCA6). The results demonstrate a critical relationship between verbal working memory and grey matter density in superior (bilateral lobules VI and crus I of lobule VII) and inferior (bilateral lobules VIIIa and VIIIb, and right lobule IX) parts of the cerebellum. We demonstrate that distinct cerebellar regions subserve different components of the prevalent psychological model for verbal working memory based on a phonological loop. The work confirms the involvement of the cerebellum in verbal working memory and defines specific subsystems for this within the cerebellum.     

Recovery of motor and cognitive function after cerebellar lesions in a songbird – role of estrogens

In addition to its key role in complex motor function, the cerebellum is increasingly recognized to have a role in cognition. Songbirds are particularly good models for the investigation of motor and cognitive processes but little is known about the role of the songbird cerebellum in these processes. To explore cerebellar function in a songbird, we lesioned the cerebellum of adult female zebra finches and examined the effects on a spatial working memory task and on motor function during this task. There is evidence for steroid synthesis in the songbird brain and neurosteroids may have an impact on some forms of neural plasticity in adult songbirds. We therefore hypothesized that neurosteroids would affect motor and cognitive function after a cerebellar injury. We found that cerebellar lesions produced deficits in motor and cognitive aspects of a spatial task. In line with our prediction, birds in which estrogen synthesis was blocked had impaired performance in our spatial task compared with those that had estrogen synthesis blocked but estrogen replaced. There was no clear effect of estrogen replacement on motor function. We also found that lesions induced expression of the estrogen synthetic enzyme aromatase in reactive astrocytes and Bergmann glia around a cerebellar lesion. These data suggest that the cerebellum of songbirds mediates both motor and cognitive function and that estrogens may improve the recovery of cognitive aspects of cerebellar function after injury.     

Transient spatial deficit associated with bilateral lesions of the lateral mammillary nuclei

The mammillary bodies have long been implicated in spatial memory, and lesions of this structure in rats can impair some spatial memory tasks. The mammillary bodies, however, comprise two main nuclei that have different electrophysiological and anatomical properties. It is therefore possible that they have different functions. The present study determined whether selective lesions of one of these components, the lateral mammillary nucleus, are sufficient to induce spatial memory deficits. While selective lateral mammillary nuclei lesions induced deficits on a working memory task in the water maze, this impairment was milder and not as persistent as that seen with complete mammillary body lesions. Furthermore, lateral mammillary nuclei lesions did not impair T-maze alternation, which is sensitive to complete mammillary body lesions. From these results it appears that lesions confined to the lateral mammillary nuclei are sufficient to produce mild impairments when rapid, new spatial learning is at a premium. At the same time, the remaining mammillary nuclei also contribute to spatial learning, though this may be in a qualitatively different manner.     

Are some memory deficits unique to lesions of the mammillary bodies?

The role of the mammillary bodies in human memory is still in debate. A recent model of human amnesia proposes similar functions for the mammillary bodies and the hippocampus. But the main evidence for this model comes from animal studies using the delayed non-matching to sample paradigm. We describe a patient who developed a severe memory impairment after surgical removal of a germinoma. Postsurgical high resolution MRI revealed bilaterally shrunken mammillary bodies and an infarct of the left mammillary body. There were no other relevant lesions. Neuropsychological testing showed mildly impaired frontal lobe functions (executive functions, working memory and word fluency), almost intact learning and recognition, but severely impaired free and delayed recall. Experimental investigations revealed a reduced but preserved release of proactive interference and a pronounced impairment of recency and source judgments. We conclude that the mammillary bodies do play a prominent role in human memory, although the role differs slightly from that of the hippocampus.     

Cerebellar involvement in executive control

The cerebellum has long been considered to be mainly involved in motor function. In the last 20 years, evidence from neuroimaging studies and from investigations of patients with cerebellar lesions has shown that the cerebellum plays a role in a range of cognitive functions. While cerebellar contributions have been shown for learning and memory, the cerebellum has also been linked to higher order cognitive control processes frequently referred to as executive functions. Although it is widely accepted that the cerebellum contributes to cognitive processing, the nature of cerebellar involvement is not well understood. The present paper focuses on the role of the cerebellum in executive processing, reviewing findings derived from neuroimaging studies or from studies investigating deficits related to cerebellar dysfunction. As executive functions cannot be considered as a unitary concept, special emphasis is put on cerebellar contributions to different aspects of executive control such as working memory, multitasking or inhibition. Referring to models derived from motor control, possible mechanisms of cerebellar involvement in executive processing are discussed. Finally, methodological problems in assessing executive deficits in general and in assessing the cerebellar contribution to executive processing in particular are addressed.     

Are Some Memory Deficits Unique to Lesions of the Mammillary Bodies?

The role of the mammillary bodies in human memory is still in debate. A recent model of human amnesia proposes similar functions for the mammillary bodies and the hippocampus. But the main evidence for this model comes from animal studies using the delayed non-matching to sample paradigm. We describe a patient who developed a severe memory impairment after surgical removal of a germinoma. Postsurgical high resolution MRI revealed bilaterally shrunken mammillary bodies and an infarct of the left mammillary body. There were no other relevant lesions. Neuropsychological testing showed mildly impaired frontal lobe functions (executive functions, working memory and word fluency), almost intact learning and recognition, but severely impaired free and delayed recall. Experimental investigations revealed a reduced but preserved release of proactive interference and a pronounced impairment of recency and source judgments. We conclude that the mammillary bodies do play a prominent role in human memory, although the role differs slightly from that of the hippocampus.     

Have we been ignoring the elephant in the room? Seven arguments for considering the cerebellum as part of addiction circuitry

Addiction involves alterations in multiple brain regions that are associated with functions such as memory, motivation and executive control. Indeed, it is now well accepted that addictive drugs produce long-lasting molecular and structural plasticity changes in corticostriatal-limbic loops. However, there are brain regions that might be relevant to addiction other than the prefrontal cortex, amygdala, hippocampus and basal ganglia. In addition to these circuits, a growing amount of data suggests the involvement of the cerebellum in many of the brain functions affected in addicts, though this region has been overlooked, traditionally, in the addiction field. Therefore, in the present review we provide seven arguments as to why we should consider the cerebellum in drug addiction. We present and discuss compelling evidence about the effects of drugs of abuse on cerebellar plasticity, the involvement of the cerebellum in drug-induced cue-related memories, and several findings showing that the instrumental memory and executive functions also recruit the cerebellar circuitry. In addition, a hypothetical model of the cerebellum's role relative to other areas within corticostriatal-limbic networks is also provided. Our goal is not to review animal and human studies exhaustively but to support the inclusion of cerebellar alterations as a part of the physiopathology of addiction disorder.     

Corticotropin releasing factor in the embryonic mouse cerebellum

Corticotropin releasing factor (CRF) is a 41 amino acid peptide that has been localized throughout the mouse cerebellum on postnatal day (P0). The wide-spread distribution of CRF within this brain region at birth suggests that it likely is present during embryonic stages of development. Thus, the intent of this study was to use immunohistochemical techniques to determine when CRF is first present in the cerebellar anlage, to analyze its distribution within the developing cerebellum, and to correlate these findings with early events in cerebellar ontogeny. CRF can first be detected in the cerebellum on embryonic day (E) 10 in scattered puncta that appear to approximate cell bodies throughout the cerebellar plate. Between E11 and E14 the number of puncta increase in the intermediate zone and more dorsal aspect of the cerebellum and decrease in the ventricular zone. At E14, in addition to the puncta, lightly immunolabeled cell bodies are observed in the ventricular zone. Just prior to birth at E17, CRF-immunoreactive varicosities distribute along the multitiered Purkinje cell layer and the intermediate zone. The CRF-positive cell bodies increase in number and intensity of staining. The majority remain within the ventricular zone, although a few also are present in the intermediate zone; it is postulated that these may be glial cells or neurons that are transiently expressing CRF. In conclusion, CRF-positive punctate elements derived from an as yet unknown source are present in the embryonic cerebellum just prior to and during the birth of Purkinje cells and nuclear neurons. The presence of this peptide at this critical stage of cerebellar development and its continued expression throughout the postnatal period of ontogeny suggests that CRF may play an important developmental role.     

The anatomy of fear learning in the cerebellum: A systematic meta-analysis

Recent neuro-imaging studies have implicated the cerebellum in several higher-order functions. Its role in human fear conditioning has, however, received limited attention. The current meta-analysis examines the loci of cerebellar contributions to fear conditioning in healthy subjects, thus mapping, for the first time, the neural response to conditioned aversive stimuli onto the cerebellum. By using the activation likelihood estimation (ALE) technique for analyses, we identified several distinct regions in the cerebellum that activate in response to the presentation of the conditioned stimulus: the cerebellar tonsils, lobules HIV–VI, and the culmen. These regions have separately been implicated in fear acquisition, consolidation of fear memories and expression of conditioned fear responses. Their specific role in these processes may be attributed to the general contribution of cerebellar cortical networks to timing and prediction. Our meta-analysis highlights the potential role of the cerebellum in human cognition and emotion in general, and addresses the possibility how deficits in associative cerebellar learning may play a role in the pathogenesis of anxiety disorders. Future studies are needed to further clarify the mechanistic role of the cerebellum in higher order functions and neuropsychiatric disorders.     

A rare case of cerebellar agenesis: a probabilistic Constrained Spherical Deconvolution tractographic study

Aim of this study is to show the potential of probabilistic tractographic techniques, based on the Constrained Spherical Deconvolution (CSD) algorithms, in recognizing white matter fiber bundle anomalies in patients with complex cerebral malformations, such as cerebellar agenesis. The morphological and tractographic study of a 17-year-old male patient affected by cerebellar agenesis was performed by using a 3Tesla MRI scanner. Genetic and neuropsychological tests were carried out. An MRI morphological study showed the absence of both cerebellar hemispheres and the flattening of the anterior side of the pons. Moreover, it showed a severe vermian hypoplasia with a minimal vermian residual. The study recognized two thin cerebellar remnants, medially in contact with the small vermian residual, at the pontine level. The third ventricle, morphologically normal, communicated with a permagna cerebello-medullary cistern. Probabilistic CSD tractography identified some abnormal and aberrant infratentorial tracts, symmetrical on both sides. In particular, the transverse pontine fibers were absent and the following tracts with aberrant trajectories have been identified: “cerebello-thalamic” tracts; “fronto-cerebellar” tracts; and ipsilateral and contralateral “spino-cerebellar” tracts. Abnormal tracts connecting the two thin cerebellar remnants have also been detected. There were no visible alterations in the main supratentorial tracts in either side. Neuropsychiatric evaluation showed moderate cognitive-motor impairment with discrete adaptive compensation. Probabilistic CSD tractography is a promising technique that overcome reconstruction biases of other diffusion tensor-based approaches and allowed us to recognize, in a patient with cerebellar agenesis, abnormal tracts and aberrant trajectories of normally existing tracts.     

The effects of cerebellar damage on maze learning in animals

The role of the cerebellum in spatial learning has recently been investigated in genetically and non-genetically lesioned animal models, particularly in water mazes, in view of the minimal impact such lesions exert on swimming movements. A dissociation between place and cued learning in the Morris water maze has been observed in several models, including cerebellar mutant mice (Rora(sg), Nna1(pcd-1J), nervous), rats with lesions of either the lateral cerebellar cortex or the dentate nucleus, and rats with selective Purkinje cell loss caused by intracerebroventricular injections of OX-7-saporin, confirming the hypothesis that cerebellar damage may cause a cognitive deficit independently of fine motor control. In addition, the results of hemicerebellectomized rats indicate the probable involvement of the cerebellum in working memory and the procedural aspect of maze learning. The findings of impaired maze learning in cerebellar-lesioned mice and rats are concordant with those of deficient visuospatial functions in patients with cerebellar atrophy. The spatial deficits may be ascribed to altered metabolic activity in cerebellar-related pathways.     

Neurotensin immunoreactivity in the human cingulate gyrus, hippocampal subiculum and mammillary bodies. Its potential role in memory processing

Neurotensin immunoreactive neurons comprise the majority of large perikarya in the human subiculum and project axons to the alveus, fimbria, fornix and neuropil of the mammillary bodies. These regions are prominently involved in conditions such as Wernicke's and Alzheimer's disease in which memory is impaired. Neurotensin has potential significance as a peptide in a human brain circuit which may serve a role in memory processing.     

Cerebellar Contributions to Verbal Working Memory

There is increasing evidence for a cerebellar role in working memory. Clinical research has shown that working memory impairments after cerebellar damage and neuroimaging studies have revealed task-specific activation in the cerebellum during working memory processing. A lateralisation of cerebellar function within working memory has been proposed with the right hemisphere making the greater contribution to verbal processing and the left hemisphere for visuospatial tasks. We used continuous theta burst stimulation (cTBS) to examine whether differences in post-stimulation performance could be observed based on the cerebellar hemisphere stimulated and the type of data presented. We observed that participants were significantly less accurate on a verbal version of a Sternberg task after stimulation to the right cerebellar hemisphere when compared to left hemisphere stimulation. Performance on a visual Sternberg task was unaffected by stimulation of either hemisphere. We discuss our results in the context of prior studies that have used cerebellar stimulation to investigate working memory and highlight the cerebellar role in phonological encoding.     

Possible mechanism for transfer of motor skill learning: implication of the cerebellum

Transfer of learning takes place whenever our previous knowledge and skills affect the way in which new knowledge and skills are learned. The magnitude of transfer may depend on how prior memory is retrieved so that it may be relevant and usable in the present in terms of internal representation. This review highlights the power of neuroimaging techniques such as positron emission tomography (PET) to identify the underlying neuronal system of intermanual transfer by showing the asymmetry in the system for the same motor skill between hands. The review focuses on cerebellar cross-activation, cerebellar activation contralateral to the active hand, which would contribute to intermanual transfer of monkey tool-use learning, together with the fronto-parietal cortical circuit. Finally, this article proposes the relationship between the cerebellum and the possible mechanism underlying non-specific transfer that allows thinking in a flexible and productive manner.