Clustering of Parkinson subtypes reveals strong influence of DRD2 polymorphism and gender.

Most classification approaches for idiopathic Parkinson's disease subtypes primarily focus on motor and non-motor symptoms. Besides these characteristics, other features, including gender or genetic polymorphism of dopamine receptors are potential factors influencing the disease's phenotype. By utilizing a kmeans-clustering algorithm we were able to identify three subgroups mainly characterized by gender, DRD2 Taq1A (rs1800497) polymorphism-associated with changes in dopamine signaling in the brain-and disease progression. A subsequent regression analysis of these subgroups further suggests an influence of their characteristics on the daily levodopa dosage, an indicator for medication response. These findings could promote further enhancements in individualized therapies for idiopathic Parkinson's disease.

Axonal degeneration in Parkinson's disease - Basal ganglia circuitry and D2 receptor availability.

Basal ganglia (BG) circuitry plays a crucial role in the control of movement. Degeneration of its pathways and imbalance of dopaminergic signalling goes along with movement disorders such as Parkinson's disease. In this study, we explore the interaction of degeneration in two BG pathways (the nigro-striatal and dentato-pallidal pathway) with D2 receptor signalling to elucidate an association to motor impairment and medication response. Included in the study were 24 parkinsonian patients [male, 62 years (± 9.3 SD)] compared to 24 healthy controls [male, 63 years (± 10.2 SD)]; each participant passed through three phases of the study (i) acquisition of metadata/clinical testing, (ii) genotyping and (iii) anatomical/diffusion MRI. We report a decline in nigro-striatal (p < .003) and dentato-pallidal (p < .0001) connectivity in the patients compared to controls, which is associated with increasing motor impairment (relating to nigro-striatal, r = -0.48; p < .001 and dentato-pallidal connectivity, r = -0.36; p = .035). Given, that variations of the ANKK1 Taq1 (rs 1,800,497) allele alters dopamine D2-dependent responses, all participants were genotyped respectively. By grouping patients (and controls) according to their ANKK1 genotype, we demonstrate a link between D2 receptor signalling and decline in connectivity in both investigated pathways for the A1- variant (nigro-striatal pathway: r = -0.53; p = .012, dentato-pallidal pathway: r = -0.62; p = .0012). In patients with the A1+ variant, we only found increased brain connectivity in the dentato-pallidal pathway (r = 0.71; p = .001) correlating with increasing motor impairment, suggesting a potentially compensatory function of the cerebellum. Related to medication response carriers of the A1+ variant had a better drug effect associated with stronger brain connectivity in the nigro-striatal pathway (r = 0.54; p < .02); the A1- group had a good medication response although nigro-striatal connectivity was diminished (r = -0.38; p < .05); these results underscore differences in receptor availability between both groups in the nigro-striatal pathway. No effect onto medication response was found in the dentato-pallidal pathway (p > .05). Interplay between basal ganglia connectivity and D2 receptor availability influence the clinical presentation and medication response of parkinsonian patients. Furthermore, while current models of basal-ganglia function emphasize that balanced activity in the direct and indirect pathways is required for normal movement, our data highlight a role of the cerebellum in compensating for physiological imbalances in this respect.

Dopamine substitution alters effective connectivity of cortical prefrontal, premotor, and motor regions during complex bimanual finger movements in Parkinson's disease.

Bimanual coordination is impaired in Parkinson's disease (PD), affecting patients' quality of life. Besides dysfunction of the basal ganglia network, alterations of cortical oscillatory coupling, particularly between prefrontal and (pre-)motoric areas, are thought to underlie this impairment. Here, we studied 16 PD patients OFF and ON medication and age-matched healthy controls recording high-resolution electroencephalography (EEG) during performance of spatially coupled and uncoupled bimanual finger movements. Dynamic causal modeling (DCM) for induced responses was used to infer task-induced effective connectivity within a network comprising bilateral prefrontal cortex (PFC), lateral premotor cortex (lPM), supplementary motor area (SMA), and primary motor cortex (M1). Performing spatially coupled movements, excitatory left-hemispheric PFC to lPM coupling was significantly stronger in controls compared to unmedicated PD patients. Levodopa-induced enhancement of this connection correlated with increased movement accuracy. During performance of spatially uncoupled movements, PD patients OFF medication exhibited inhibitory connectivity from left PFC to SMA. Levodopa intake diminished these inhibitory influences and restored excitatory PFC to lPM coupling. This restoration, however, did not improve motor function. Concluding, our results indicate that lateralization of prefrontal to premotor connectivity in PD can be augmented by levodopa substitution and is of compensatory nature up to a certain extent of complexity.

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.

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.

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.