Date Published: July 10, 2017
Publisher: Public Library of Science
Author(s): Giusy Olivito, Michael Dayan, Valentina Battistoni, Silvia Clausi, Mara Cercignani, Marco Molinari, Maria Leggio, Marco Bozzali, Vince Grolmusz.
Over the last decades, the importance of cerebellar processing for cortical functions has been acknowledged and consensus was reached on the strict functional and structural cortico-cerebellar interrelations. From an anatomical point of view strictly contralateral interconnections link the cerebellum to the cerebral cortex mainly through the middle and superior cerebellar peduncle. Diffusion MRI (dMRI) based tractography has already been applied to address cortico-cerebellar-cortical loops in healthy subjects and to detect diffusivity alteration patterns in patients with neurodegenerative pathologies of the cerebellum. In the present study we used dMRI-based tractography to determine the degree and pattern of pathological changes of cerebellar white matter microstructure in patients with focal cerebellar lesions. Diffusion imaging and high-resolution volumes were obtained in patients with left cerebellar lesions and in normal controls. Middle cerebellar peduncles and superior cerebellar peduncles were reconstructed by multi fiber diffusion tractography. From each tract, measures of microscopic damage were assessed, and despite the presence of unilateral lesions, bilateral diffusivity differences in white matter tracts were found comparing patients with normal controls. Consistently, bilateral alterations were also evidenced in specific brain regions linked to the cerebellum and involved in higher-level functions. This could be in line with the evidence that in the presence of unilateral cerebellar lesions, different cognitive functions can be affected and they are not strictly linked to the side of the cerebellar lesion.
Over the past two decades, the role of the cerebellum in cognition has been widely demonstrated [1–4]. Anatomically, cerebello-cortical-cerebellar connections are known to be strictly controlateral and to be spatially and functionally organized in distinct parallel loops [5–6]. The afferent system consists of cortico-pontine fibers projecting from cerebral cortex areas to the pontine nuclei and of ponto-cerebellar fibers, crossing the midline to enter the cerebellum by means of the contralateral Middle Cerebellar Peduncle (MCP) . Conversely, the Superior Cerebellar Peduncle (SCP) is well known to be the efferent fibers system from the cerebellum [8–9] decussating at the level of the midbrain and projecting to motor and associative cortices via the thalamus [5–6, 10]. This complex neural system allows the cerebellum to receive, optimize and send back the information that it receives from cerebral cortex regions to accomplish motor and cognitive functions successfully. Functional studies with healthy subjects also support the anatomical evidence of functionally related parallel cortico-cerebellar loops . Based on recent evidence from a Voxel Based Morphometry (VBM) study, the clinical alterations consequent to a focal cerebellar lesion are associated with specific structural modifications in cerebello-related areas of the cerebral cortex . The interruption of cerebello-thalamo-cortical pathways has been reported as the mechanism responsible for crossed cerebello-cerebral diaschisis (CCCD) [13– 15]. In this context, the functional impairment in the cerebral regions contralateral to the cerebellar lesion has been explained as a functional depression of cerebello-ponto-thalamo-cerebral pathways . Thus, it is possible to hypothesize that a disruption of this pathway is responsible for the functional depression of those cerebral regions from where a motor or cognitive command originates, to reach the cerebellum which in turn redistributes new cerebellar-processed information back to the same cerebral regions. Since MCP and SCP are the feedback and feedforward limbs of the cerebello-cortical system it is reasonable to think that cerebellar white matter (WM) alterations, secondary to the presence of cerebellar damage, may affect the cerebello-cortical interaction and result in hypoactivity of supratentorial brain regions accounting for the various clinical dysfunctions typically observed [16–17]. It follows that investigating cerebellar white matter microstructure is required to understand the cerebello-cortical alterations subtending the complex cerebellar cognitive affective syndrome . Diffusion Tensor Imaging (DTI) has proven to be a valuable tool for investigating brain white matter since it can probe tissue microstructure by assessing the displacement of water molecules within specific WM tracts . Although diffusion-derived indices provide a very indirect measure of microstructural properties, they have been associated with specific white matter abnormalities. Among them, Radial Diffusivity (RD) has been shown to be positively correlated with fiber disruption [19–20]. Thanks to its ability to reconstruct 3-dimensional fiber bundles (a process known as tractography), DTI also appears relevant in providing a model of brain connectivity through which brain disconnection can be studied. Recently, the ability of DTI tractography to map and quantify the whole trajectory of different cortico-cerebellar pathways has been demonstrated in normal adult brain [8, 21–22] as well as in patients with ataxia and cerebellar tremor . A probabilistic atlas of cerebellar WM has been recently proposed contributing to a better understanding of cerebellar WM architecture . One well-known limitation of DTI tractography is the inherent assumption of a single fiber direction per voxel, which limits its applicability to white matter areas of crossing-fibers. In order to compensate for this limitation a number of higher order models of diffusion have been introduced (see Alexander, 2005 for a review), and applied recently to reconstruct cerebellar peduncles .
In the present study we aimed at reconstructing MCP and SCP and describing the pattern of white matter alterations associated with unilateral cerebellar lesions. We performed diffusion-based tractography to assess the sub-voxel organization/disruption of these tracts. Previous DTI studies have identified and isolated the cerebellar projections to prefrontal and parietal cortices in healthy subjects [20–22], and have shown specific RD changes in the cerebellar peduncles of patients with hereditary or sporadic cerebellar ataxia [40–41, 25]. To our knowledge, this is the first study to examine the structural pattern of MCP and SCP in patients with unilateral cerebellar lesions. In terms of integrity, white matter architecture of MCP and SCP showed a specific pattern of diffusion changes. The most intriguing finding was that, in spite of the unilaterality of the lesion, microstructural changes (where by microstructural we mean with no corresponding abnormalities visible on conventional scan) were present bilaterally in MCP and SCP at least at group level. This is more interesting taking into account that macroscopic abnormalities (i.e., visible lesions) were present only unilaterally on MRI scans of all subjects. Multiple diffusion parameters were analyzed and selective diffusivity changes were detected. Overall, an increase of RD and MD without significant changes in AD was found in both MCP and SCP bilaterally with FA significantly decreased only in the ipsilesional MCP. Increased MD and decreased FA have been typically reported in chronic ischemic lesions (> 2 weeks) [38, 42]. This is consistent with our sample; 6 out of 9 patients presented a cerebellar chronic ischemic lesion. On the other hand RD and AD provide information on myelin and axon conditions. Specifically myelination affects RD, [20, 43–44], while axonal damage affects AD. Thus, our findings indicate prevalent bilateral myelin damage with relative axonal sparing. Focal cerebellar lesions have been described to result in impaired higher cognitive functions, associated with structural modifications in cerebral cortex regions functionally linked to the cerebellar lesioned areas [6, 12]. Specifically, a focal cerebellar lesion has been described to result in a functional impairment of the contralateral cerebral cortex (crossed cerebello-cerebral diaschisis) [14–15, 45–46], consistent with the prominent anatomical properties of the cerebello-cerebral projections that for the most part are crossed [6, 10]. However, in the present study cerebral regions ipsilateral to the lesioned cerebellum, namely caudate nucleus and putamen, were also found to show significant GM alterations. Similar ipsilesional changes have also been observed in the cerebral cortex in a previous VBM study . Bilateral cerebellar influences over cerebral cortex are also supported by lesional studies in rodents showing abnormal activity in the ipsilesional sensorimotor cortex  not to mention that ipsilateral connections between cerebellum and cerebral cortex have also been shown [48–49]. In light of this evidence, it is reasonable to hypothesize that not only contralateral but also ipsilateral networks may suffer from a unilateral damage of the cerebellum. Present findings, indicating changes in the cerebellar peduncles sub-voxel structure bilaterally in face of a unilateral cerebellar lesion, may impact our understating of cerebro-cerebellar interplay. As most of the recruited patients had a lesion in the left cerebellum, we cannot conclude with certainty that a right-side lesion would result in the same pattern of damage. Further investigations are needed to confirm that these findings can be generalized.