Esther Annegret Pelzer

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 Parkinsons 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.

Basal ganglia and cerebellar interconnectivity within the human thalamus

Basal ganglia and the cerebellum are part of a densely interconnected network. While both subcortical structures process information in basically segregated loops that primarily interact in the neocortex, direct subcortical interaction has been recently confirmed by neuroanatomical studies using viral transneuronal tracers in non-human primate brains. The thalamus is thought to be the main relay station of both projection systems. Yet, our understanding of subcortical basal ganglia and cerebellar interconnectivity within the human thalamus is rather sparse, primarily due to limitation in the acquisition of in vivo tracing. Consequently, we strive to characterize projections of both systems and their potential overlap within the human thalamus by diffusion MRI and tractography. Our analysis revealed a decreasing anterior-to-posterior gradient for pallido-thalamic connections in: (1) the ventral-anterior thalamus, (2) the intralaminar nuclei, and (3) midline regions. Conversely, we found a decreasing posterior-to-anterior gradient for dentato-thalamic projections predominantly in: (1) the ventral-lateral and posterior nucleus; (2) dorsal parts of the intralaminar nuclei and the subparafascicular nucleus, and (3) the medioventral and lateral mediodorsal nucleus. A considerable overlap of connectivity pattern was apparent in intralaminar nuclei and midline regions. Notably, pallidal and cerebellar projections were both hemispherically lateralized to the left thalamus. While strikingly consistent with findings from transneuronal studies in non-human primates as well as with pre-existing anatomical studies on developmentally expressed markers or pathological human brains, our assessment provides distinctive connectional fingerprints that illustrate the anatomical substrate of integrated functional networks between basal ganglia and the cerebellum. Thereby, our findings furnish useful implications for cerebellar contributions to the clinical symptomatology of movement disorders.

Ageing changes effective connectivity of motor networks during bimanual finger coordination.

Bimanual finger coordination declines with age. However, relatively little is known about the neurophysiological alterations in the motor-system causing this decline. In the present study, we used 128-channel electroencephalography (EEG) to evaluate causal interactions of cortical, motor-related brain areas. Right-handed young and elderly subjects performed complex temporally and spatially coupled as well as temporally coupled and spatially uncoupled finger tappings. Employing dynamic causal modelling (DCM) for induced responses, we inferred task-induced effective connectivity within a core motor network comprising bilateral primary motor cortex (M1), lateral premotor cortex (lPM), supplementary motor area (SMA), and prefrontal cortex (PFC). Behavioural analysis showed significantly increased error rates and performance times for elderly subjects, confirming that motor functions decrease with ageing. Additionally, DCM analysis revealed that this age-related decline can be associated with specific alterations of interhemispheric and prefrontal to premotor connectivity. Young and elderly subjects exhibited inhibitory left to right M1-M1 coupling during performance of temporally and spatially coupled movements. Effects of ageing on interhemispheric connectivity particularly emerged when movements became spatially uncoupled. Here, elderly participants still expressed inhibitory left to right M1-M1 coupling, whereas no such connection was present in the young. Furthermore, ageing affected prefrontal to premotor connectivity. In all conditions, elderly subjects showed significant couplings from left PFC to left lPM. In contrast, young participants exhibited left PFC to SMA connections. These results demonstrate that (i) in spatially uncoupled movements interhemispheric M1-connectivity increases with age and (ii) support the idea that ageing is associated with enhanced lateral prefrontal to premotor coupling (PFC to lPM) and hypoactivation of a medial pathway (PFC to SMA) within the dominant hemisphere.

The differentiated networks related to essential tremor onset and its amplitude modulation after alcohol intake

The dysregulation of endogenous rhythms within brain networks have been implicated in a broad range of motor and non-motor pathologies. Essential tremor (ET), classically the purview of a single aberrant pacemaker, has recently become associated with network-level dysfunction across multiple brain regions. Specifically, it has been suggested that motor cortex constitutes an important node in a tremor-generating network involving the cerebellum. Yet the mechanisms by which these regions relate to tremor remain a matter of considerable debate. We sought to discriminate the contributions of cerebral and cerebellar dysregulation by combining high-density electroencephalography with subject-specific structural MRI. For that, we contrasted ET with voluntary (mimicked) tremor before and after ingestion of alcohol to regulate the tremorgenic networks. Our results demonstrate distinct loci of cortical tremor coherence, most pronounced over the sensorimotor cortices in healthy controls, but more frontal motor areas in ET-patients consistent with a heightened involvement of the supplementary motor area. We further demonstrate that the reduction in tremor amplitude associated with alcohol intake is reflected in altered cerebellar - but not cerebral - coupling with movement. Taken together, these findings implicate tremor emergence as principally associated with increases in activity within frontal motor regions, whereas modulation of the amplitude of established tremor relates to changes in cerebellar activity. These findings progress a mechanistic understanding of ET and implicate network-level vulnerabilities in the rhythmic nature of communication throughout the brain.

Classification of symptom-side predominance in idiopathic Parkinson's disease.

Asymmetry of symptom onset in Parkinson’s disease (PD) is strongly linked to differential diagnosis, progression of disease, and clinical manifestation, suggesting its importance in terms of specifying a therapeutic strategy for each individual patient. To scrutinize the predictive value of this consequential clinical phenomenon as a neuromarker supporting a personalized therapeutic approach, we modeled symptom-side predominance at disease onset based on brain morphology assessed with magnetic resonance (MR) images by utilizing machine learning classification. The integration of multimodal MR imaging data into a multivariate statistical model led to predict left- and right-sided symptom onset with an above-chance accuracy of 96%. By absolute numbers, all but one patient were correctly classified. Interestingly, mainly hippocampal morphology supports this prediction. Considering a different disease formation of this single outlier and the strikingly high classification, this approach proves a reliable predictive model for symptom-side diagnostics in PD. In brief, this work hints toward individualized disease-modifying therapies rather than symptom-alleviating treatments.

Thalamic interactions of cerebellum and basal ganglia

Cerebellum and basal ganglia are reciprocally interconnected with the neocortex via oligosynaptic loops. The signal pathways of these loops predominantly converge in motor areas of the frontal cortex and are mainly segregated on subcortical level. Recent evidence, however, indicates subcortical interaction of these systems. We have reviewed literature that addresses the question whether, and to what extent, projections of main output nuclei of basal ganglia (reticular part of the substantia nigra, internal segment of the globus pallidus) and cerebellum (deep cerebellar nuclei) interact with each other in the thalamus. To this end, we compiled data from electrophysiological and anatomical studies in rats, cats, dogs, and non-human primates. Evidence suggests the existence of convergence of thalamic projections originating in basal ganglia and cerebellum, albeit sparse and restricted to certain regions. Four regions come into question to contain converging inputs: (1) lateral parts of medial dorsal nucleus (MD); (2) parts of anterior intralaminar nuclei and centromedian and parafascicular nuclei (CM/Pf); (3) ventromedial nucleus (VM); and (4) border regions of cerebellar and ganglia terminal territories in ventral anterior and ventral lateral nuclei (VA–VL). The amount of convergences was found to exhibit marked interspecies differences. To explain the rather sparse convergences of projection territories and to estimate their physiological relevance, we present two conceivable principles of anatomical organization: (1) a “core-and-shell” organization, in which a central core is exclusive to one projection system, while peripheral shell regions intermingle and occasionally converge with other projection systems and (2) convergences that are characteristic to distinct functional networks. The physiological relevance of these convergences is not yet clear. An oculomotor network proposed in this work is an interesting candidate to examine potential ganglia and cerebellar subcortical interactions.

Structural differences in impaired verbal fluency in essential tremor patients compared to healthy controls

We wanted to identify differences in grey and white matter in essential tremor patients compared to controls in the non‐motor domain, using the example of impaired verbal fluency.

Deep brain stimulation in rapidly progressive parkinson-dystonia syndrome due to mitochondrial disorder

Although Parkinson’s disease (PD) and dystonia can effectively be treated with drug therapy and deep brain stimulation (DBS), effective treatment for movement disorders in mitochondrial disorders are rare. In PD as drug therapy becomes less effective motor deficits such as tremor, rigidity and bradykinesia can effectively be treated with DBS at targets points like the subthalamic nucleus (STN) and the globus pallidus internus (GPI); in dystonia DBS in the GPI has been employed in both primary and secondary forms of dystonia. In this reportwedescribe apatientwith amitochondrial disorder (MD), who was treated with palliative GPI-DBS and later with bilateral DBS in the nucleus ventralis oralis anterior thalami (VOA)which resulted in reduced pain and rigidity. In this report we discuss the efficiency of DBS of two target points (GPI, VOA) in MD.

Clinical role of a subcortical communication

Subcortical communication is an important underlying feature for the smooth performance of motor behaviour. Especially movement disorders like Parkinson’s disease show impairment in the basal-ganglio-thalamic and cerebello-thalamic communication; but also an impairment of the direct communication between these two structures has been proposed. In this review we highlight important clinical findings concerning the pathological communication between these subcortical structures; additionally we propose a new hypothesis in the development of neurodegenerative disease: we assume that axon degeneration is crucially implicated in the development of parkinsonian symptoms and link the current findings to the development of pathological oscillatory activity. New techniques like probabilistic tractography now offer the possibility to in vivo measure axon degeneration by the determination of connectivity decline and allow the combination with electrophysiological recording. We hypothesize that a change in frequency bands in oscillatory activity might be a product of underlying axonal degeneration; moreover axonal degeneration might be worsened by pathological oscillatory activity resulting in a vicious circle. The thalamus, as main relay station between the basal ganglia and the cerebellum seems to be involved in this disease pathology in Parkinson’s disease.